CNS Spectr. 2007;12(8 Suppl 11):1-16

This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.  

Credit Designation

The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)^TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement 

It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer reviewed and approved by Eric Hollander, MD, Chair and Professor of Psychiatry at The Mount Sinai School of Medicine. Review Date: July 18, 2007

Statement of Need and Purpose

Schizophrenia is among the world’s top 10 causes of long-term disability. The clinical picture includes a range of symptoms such as delusions, hallucinations, agitation, suspiciousness, hostility, conceptual disorganization, blunted affect, emotional and social withdrawal, lack of spontaneity, poverty of speech, and a wide range of neurocognitive deficits. Agitation is an important therapeutic target in the acute and/or emergent setting, as well as for longer-term care of patients with schizophrenia. Rapid and effective control of agitation is necessary to minimize danger both to patients and their caregivers. Acute emergent presentations of schizophrenia often include hallucinations, delusions, as well as thought and speech disorders. Pharmacologic management of acute agitation consists of atypical antipsychotics, typical antipsychotics, and benzodiazepines. The selection of a specific agent (or combination of agents) should be guided by etiologic considerations, efficacy of the drug(s), side effects, potential drug interactions, and drug formulation. Preliminary evidence suggests that atypical antipsychotics effectively reduce agitation, are better tolerated, and have fewer side effects than typical antipsychotics. After an acute episode, atypical agents help to ease the transition from intramuscular to oral medication to promote ongoing treatment. New intramuscular atypical antipsychotic formulations offer evidence of being at least as effective as typical antipsychotics in controlling agitation and therefore should be considered first line therapy in agitated schizophrenic patients.

Target Audience

This activity is designed to meet the educational needs of psychiatrists.

Goal of the Activity
• To educate physicians on the definition and evaluation of acute agitation as well as the available pharmacotherapeutic options for acute management of agitation.

Learning Objectives

• Recognize the symptoms of acute agitation.
• Assess the safety considerations for treatment of acute agitation.
• Determine efficacious pharmacologic and nonpharmacologic treatment options for acute agitation.

Faculty Affiliations and Disclosures

Joseph Battaglia, MD, is assistant professor of psychiatry at Albert Einstein College of Medicine and clinical director of the Bronx Psychiatric Center in Bronx, New York. Dr. Battaglia reports no financial, academic, or other interest in any organization that may pose a conflict of interest.

Delbert G. Robinson, MD, is an associate investigator at the Feinstein Institute for Medical Research of the North Shore Long Island Jewish Health System in Manhasset, New York, and associate professor of psychiatry and behavioral sciences at Albert Einstein College of Medicine in Bronx, New York. Dr. Robinson receives research support from Bristol-Myers Squibb and Janssen.   

Leslie Citrome, MD, MPH, is professor of psychiatry at the New York University School of Medicine and director of the Clinical Research and Evaluation Facility at the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York. Dr. Citrome is a consultant and/or advisor to, receives honoraria and/or research support from, and owns stock in Bristol-Myers Squibb, Eli Lilly, and Pfizer.

Acknowledgment of Commercial Support

Funding for this activity has been provided by an educational grant from Eli Lilly and Company.

Peer Reviewers

David L. Ginsberg, MD, receives honoraria and research support from AstraZeneca, Cyberonics, and GlaxoSmithKline.

Eric Hollander, MD, reports no financial, academic, or other support that may pose a conflict of interest.

To Receive Credit for this Activity

Read this supplement, reflect on the information presented, and complete the CME quiz and evaluation. To obtain credit, you should score 70% or better. Early submission of this posttest is encouraged to measure outcomes for this CME activity. Please submit this posttest by August 1, 2009 to be eligible for credit.

Release date: August 1, 2007

Termination date: August 31, 2009

Abstract

Acute agitation is a nonspecific term applied to an array of syndromes and behaviors. It is frequently defined as an increase in psychomotor activity, aggression, disinhibition/impulsivity, and irritable or labile mood. Etiologies of acute agitation include medical disorders, delirium, substance intoxication or withdrawal, psychiatric disorders, and medication side effects. Treatment of acute agitation requires both environmental and pharmacologic intervention. Patients should be calmed with sedating agents early in the course of treatment, allowing for diagnostic tests to take place. Failure to correctly diagnose causes of agitation may lead to delayed treatment for serious conditions, and can even exacerbate agitation.The most common cause of agitation in patients with schizophrenia is psychotic relapse due to medication nonadherence. Pharmacologic treatment options for these patients include lorazepam and antipsychotic agents. Lorazepam causes nonspecific sedation and treats some substance withdrawal, but has little effect on psychosis. First-generation antipsychotics treat psychosis and, at high enough doses, cause sedation, but may induce extrapyramidal side effects (EPS). Some second-generation antipsychotics have been approved for the treatment of agitation in schizophrenia. These agents treat psychosis with a favorable EPS profile, but are comparatively expensive and cause risks such as hypotension. However, avoiding EPS may reduce patients’ resistance to antipsychotic treatment.

In this expert roundtable supplement, Joseph Battaglia, MD, provides an overview of the definition of acute agitation. Next, Delbert G. Robinson, MD, outlines evaluation methods for actue agitation. Finally, Leslie Citrome, MD, MPH, reviews interventions for acute and ongoing management of agitation.

Concerns Surrounding the Definition of Acute Agitation

Joseph Battaglia, MD

Definition of Agitation

Agitation, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR),¹ focuses on psychomotor agitation. It is described as excessive motor activity associated with a feeling of inner tension. The activity is usually nonproductive and repetitious, and consists of behaviors such as pacing, fidgeting, wringing of the hands, pulling of clothes, and inability to sit still. In contrast, the definition of agitation in the literature varies with different illnesses, such as dementia, traumatic brain injury, schizophrenia, and bipolar disorder. However, the terms used to define agitation share the following factors: increase in psychomotor activity; aggression; disinhibition/impulsivity; and irritable, anxious, or labile mood (Slide 1). Unfortunately, these are vague definitions. More precise definitions would allow for better outcome measures and more reliable study designs to accurately determine the efficacy and effectiveness of treatment interventions.

Scales Used in the Assessment of Agitation

Several new behavioral scales have recently been used to assess treatment interventions in schizophrenia. The Behavioral Activity Rating Scale (BARS)² was first used in a study of ziprasidone intramuscular (IM). The BARS is composed of a single item with seven categories ranging from “difficult or unable to rouse” all the way up to “violent, requiring restraint.”  This scale is simple and can be completed quickly, after one observation. The Overt Agitation Severity Scale (OASS), designed by Yudofsky and colleagues,³ is separated into three categories—vocalization/facial movements, upper torso movement, and lower extremity movements—with four items within each of these categories. The intensity of these items is ranked and multiplied by frequency to generate a severity score. The entire assessment takes about 15 minutes. Both the BARS and the OASS have been validated for patients with psychiatric illness (Slide 2).

Another way to assess agitation is to view it as it relates to a specific illness. Schizophrenia can be conceptualized as an illness characterized by a variety of symptoms. These symptoms cluster into several groups, such as positive and negative, and these groups can be considered syndromes. Although agitation is not considered a core symptom of schizophrenia, agitation can be a feature of one or more of these symptoms, being directly related to symptom severity. Using  this model to define agitation in schizophrenia, clinicians and researchers use the Positive and Negative Syndrome Scale, Excited Component (PANSS-EC).^4-6 Here, agitation is a condition met when the threshold total score is at least 14 or 15 (depending on the study) on the five items of the  PANSS-EC—poor impulse control, tension, hostility, uncooperativeness, and excitement. This scale was used recently in the olanzapine IM and aripiprazole IM studies.

Agitation Across Diagnoses

An important but unexamined question is whether agitation in schizophrenia differs from agitation in other conditions. Behavioral scales for agitation cross diagnostic boundaries, encompassing varied pathologies such as dementia and traumatic brain injury. This suggests that either there is no difference, or there are common pathologies such as dysfunctional prefrontal cortical function leading to impulsive aggression.⁷

An interesting finding supporting this last point is a study by Quanbeck and colleagues.⁸ The authors examined the medical records of state hospital inpatients who had committed three or more assaults over a 1-year period. It was found that these behaviors were more often related to poor impulse control than to psychosis.

Some conditions that are comorbid with schizophrenia, also have symptoms with agitation as a component (Slide 3). This is the case in comorbid depression,⁹ substance abuse, obsessive-compulsive disorder, panic disorder, anxiety spectrum disorders, and posttraumatic stress disorder (PTSD).  When a comorbid condition is present, agitation can be defined using a scale specific to that illness, that measures illness severity. As an example, the Hamilton Rating Scale for Depression (HAM-D),¹⁰ has an agitation subscale which ranges from 0 (no agitation) to 4 (frank pacing with irritability). Other diagnosis-specific scales that include items relating to agitation include the following: the Montgomery-Asberg Depression Rating Scale,¹¹ the Young Mania Rating Scale,¹² and the Manic State Rating Scale for Mania.

Healthcare Regulatory Factors

An important concern about how we define agitation relates to healthcare regulatory factors. The most recent definition of chemical restraint is regulation 48313 of the Center for Medicaid and Medicare Services, written in January 2007. This regulation defines chemical restraint as “a drug or medication used as a restriction to manage the patient’s behavior or restrict the patient’s freedom of movement, and is not a standard treatment or dosage for the patient’s condition.”¹³ Use of a chemical restraint requires monitoring, as does any seclusion or restraint use.

Therefore, if we define agitation as being related to a symptom of a specific illness, it would be clear that our primary intention is to decrease symptom severity.  Otherwise, it can be inferred that our intention is primarily to control behavior by chemically restraining a patient. As an example, consider the following vignette:

A 41-year-old male with a known diagnosis of schizophrenia is admitted due to an acute exacerbation of his illness. His illness had responded well to treatment with ziprasidone 80 mg BID. His family reports that he has not been taking his medication for several weeks. He now presents with paranoia—fearing that he is about to die, hypervigilance, restlessness, and pacing rapidly with clenched fists. His physical exam is only remarkable for mild tachycardia and excessive perspiration. His laboratory workup is completely normal, including negative urine toxicology. The attending psychiatrist orders ziprasidone IM 20 mg, documenting that he is targeting the symptoms of excitement and suspiciousness, and also orders lorazepam IM 2 mg to target symptoms of tension and anxiety. He also documents that he is using both, as previous history notes that ziprasidone alone does not effectively control his symptoms. He uses the PANSS-related subscales to rate current severity. This would not be considered use of chemical restraint, as it is clear that the goal is reduction of symptom severity related to his illness. 

If this client had presented with the same clinical picture in an emergency room, but his diagnosis was unknown, administration of any of the above medication would be considered a chemical restraint and should be monitored as such to ensure the patient’s safety.

Conclusion

The term “acute agitation” is not specific to any diagnosis and does not lend itself to studying underlying conditions. Agitation can be understood as being related to symptom severity. It would be more helpful to use a diagnosis-specific scale which rates symptom severity, to clarify which symptoms are being targeted for treatment.  For schizophrenia, the PANSS has such scales, and allows for measuring targeted symptom reduction. However, in an acute setting it may not be possible to discern an underlying condition, and the best one can do is manage the agitation safely. Behavioral scales would be useful in these situations to monitor treatment effectiveness.

References

1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed text rev. Washington, DC: American Psychiatric Association; 2000.
2. Swift RH, Harrigan EP, Cappelleri JC, Kramer D, Chandler LP. Validation of the Behavioral Activity Rating Scale (BARS): a novel measure of activity in agitated patients. J Psychiatr Res. 2002;36(2):87-95.
3. Yudofsky SC, Kopecky HJ, Kunik M, Silver JM, Endicott J. The Overt Agitation Scale for the objective rating of agitation. J Neuropsychiatry Clin Neurosci. 1997;9(4):541-548.
4. Wolthaus JE, Dingemans PM, Schene AH, et al. Component structure of the positive and negative syndrome scale (PANSS) in patients with recent-onset schizophrenia and spectrum disorders. Psychopharmacology (Berl). 2000;150(4):399-403.
5. Kay SR, Sevy S. Pyramidical model of schizophrenia. Schizophr Bull. 1990;16(3):537-545.
6. Wright P, Birkett M, David SR, et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry. 2001;158(7):1149-1151.
7. Best M, Williams MJ, Coccaro EF. Evidence for a dysfunctional prefrontal circuit in patients with an impulsive aggressive disorder. Proc Natl Acad Sci U S A. 2002; 99(12):8448-8453.
8. Quanbeck CD, McDermott BE, Lam J, et al. Categorization of aggressive acts committed by chronically assaultive state hospital patients. Psychiatr Serv. 2007;58(4):521-528.
9. Schatzberg AF, DeBattista C. Phenomenology and treatment of agitation. J Clin Psychiatry. 1999;60(suppl 15):17-20.
10. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62.
11. Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389.
12. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429-435.
13. Center for Medicaid and Medicare Services. Definition of Chemical Restraint: January 2007. Regulation 483.

Delbert G. Robinson, MD

Factors to Consider in the Evaluation of the Agitated Patient

Approximately 900,000 emergency room visits per year in the United States are attributed to psychosis.¹ Although the proportion of these visits that are associated with agitation is not known, clinical experience suggests that agitation is a frequent precipitant of referral to emergency rooms. The striking number of visits for psychosis suggests the potential magnitude of the problem of agitation in patients with schizophrenia. 

Agitation has many potential causes. However, the nature of agitation may limit the clinician’s ability to perform a thorough evaluation of potential etiologies of agitation. It is important for clinicians to have a thorough knowledge of the potential causes of agitation. With this background, clinicians can target their initial evaluation to the most likely etiologies for patients whose agitation prevents a comprehensive initial evaluation. A general principle for evaluation of severely agitated patients is to seek out collateral sources of information, including family and medical records. A general psychiatric evaluation is always necessary, and laboratory tests, toxicity screens, and brain imaging may be needed as well (Slide 1).

In addition to establishing the diagnosis, it is important for clinicians to obtain information about the patient’s history of violence and medication adherence. Medication nonadherence is a common cause of schizophrenia relapse, and can lead to increased agitation. Knowing which medications a patient did or did not adhere to in the past is helpful in preparing a treatment regimen that increases the likelihood that the patient will continue it.

A history of violence is an important factor to consider for the safety of both the patient and those caring for him (eg, family members, clinicians). The relationship between agitation and violence is complex. Although there are many factors surrounding agitation that are not well understood, we do know that there is a potential for agitation to develop into overt violence, which is a major concern.

Owen and colleagues² studied 174 patients who had been violent while in a variety of inpatient units in Sydney, Australia. The patients were divided into two groups: those who had been repeatedly violent, defined as having >3 episodes of violence, and those who had infrequent episodes of violence. The researchers found that the repeatedly violent patients gave more warning signs before their violent episodes, and one of the most important warning signs was agitation. Obtaining information about recent violent behavior can be very useful. McNeil and colleagues³ studied 238 patients with a variety of diagnoses who had been involuntarily admitted to inpatient treatment.  Eighteen percent of the patients attacked others during the first 72 hours of their admission. Among the 11 patient variables examined, violence during the 2 weeks before hospitalization was the best at identifying the patients who were violent in the hospital.

Potential Causes of Agitation

Agitation has many potential causes. These etiologies can be grouped into five broad categories: (1) medical disorders; (2) delirium and dementia; (3) substance intoxication or withdrawal; (4) schizophrenia and other psychiatric disorders; and (5) medication side effects.

Medical Conditions

Among the vast number of medical disorders to consider are major diseases of the central nervous system—such as infections, tumors, and strokes—that can lead to delirium or can be associated with a disinhibition syndrome (Slide 2). Other medical conditions to consider are: (1) metabolic disorders such as electrolyte imbalances, hepatic or renal disease; (2) endocrine disorders such as hypoglycemia, hyperglycemia, and hyperthyroidism; and (3) seizures and post-ictal states.  Severe pain can lead to agitation, and assessment for pain may be difficult with patients with impaired ability to communicate. Finally, one has to consider all of the other potential medical causes of delirium and dementia, especially in elderly patients with agitation.

Substance Intoxication or Withdrawal

Another broad group of potential causes of agitation is substance intoxication or withdrawal. Intoxication with drugs such as alcohol and sedatives can lead to disinhibition. Sympathomimetic abuse or hallucinogen abuse can provoke or exacerbate psychotic symptoms. Phencyclidine (PCP) intoxication is often associated with irritability, but irritability can also be associated with alcohol intoxication or withdrawal. Agitation may also be caused by ingestion of toxic substances such as ethylene glycol (Slide 3).

Schizophrenia and Other Psychiatric Disorders

The most common cause of agitation by patients with schizophrenia is psychotic relapse, often precipitated by antipsychotic medication nonadherence. There are several core symptoms of relapse in schizophrenia that can lead to agitation. For example, patients in an agitated state may be responding to command hallucinations or acting upon paranoid delusions. Patients with catatonic excitement may present with various degrees of severe agitation (Slide 4).

Agitation can be seen in a variety of other psychiatric disorders, all of which should be included in a clinician’s differential. Both depression and mania can be associated with psychomotor agitation or psychotic symptoms that can produce agitation. Clinicians must also consider comorbid anxiety disorders. For example, panic disorder or another severe anxiety disorders might lead to agitation.

Medication Side Effects

Finally, one needs to consider the side effects of psychotropic medications. Excessive use of anticholinergic medications can cause a delirium that may be accompanied by agitation. Anticholinergic delirium should be evaluated as a cause of agitation with patients who present with cognitive disturbances and peripheral signs of anticholinergic effects such as dilated pupils, dry skin and mouth, tachycardia, constipation or urinary retention. Antipsychotic motor side effects, especially tardive dyskinesia and akathisia, may mimic agitation. Patients with tardive dyskniesia present with repetitive rapid movements. Oral-facial movements are almost always present. Movements of the trunk such as body rocking or movements of the hands or feet may be mistaken for agitation. Patients with akathisia have a subjective sense of restlessness or inability to remain still.  The motor manifestations of akathisia such as pacing or repeatedly getting up from chairs may resemble agitation. Although caused by antipsychotic treatment, increasing the dose of antipsychotic medication may suppress the movements of tardive dyskinesia. In contrast, if a patient with akathisia is presumed to have agitation and is treated with antipsychotic medications, their akathisia and the presumed agitation may be exacerbated. 

Conclusion

In summary, the most common cause of agitation by patients with schizophrenia is psychotic relapse, often precipitated by antipsychotic medication nonadherence.  However, clinicians should consider other causes of agitation in their diagnostic evaluation. Failure to correctly diagnose medical causes of agitation may lead to delayed treatment for sometimes serious conditions. Recognition of the contribution of substance abuse or other psychiatric disorders to agitation with particular patients can lead to better treatment plans for these individuals. Finally, correctly diagnosing akathisia can prevent clinicians from inappropriately increasing the dose of antipsychotic medication.

References

1. Hazlett SB, McCarthy ML, Lindner MS, Onyike CU. Epidemiology of adult psychiatric visits to US emergency departments. Acad Emerg Med. 2004;11:193-195.
2. Owen C, Tarantello C, Jones M, Tennant C.  Repetitively violent patients in psychiatric units. Psychiatr Serv. 1998;49:1458-1461
3. McNiel DE, Binder RL, Greenfield TK. Predictors of violence in civilly committed acute psychiatric patients. Am J Psychiatry. 1988;145:965-970.

Overview of Treatment

There are two components in the treatment of acute agitation: environmental interventions and pharmacologic interventions (Slide 1).¹ One environmental intervention that is relatively easy and that can be very helpful is clearing the room of other patients. It is actually much easier to move a group of calm people than to move one agitated patient. It is also important to have staff members available to manage the patient without overwhelming him or her. One staff member should interact with the patient, listen to their concerns, and allow them to “ventilate.” Restraints and seclusion should be on hand in case the patient cannot be managed safely despite the presence of many staff. The television or radio should be muted. In terms of pharmacologic intervention, nonspecific “sedating” or “calmative” agents should be offered early in the treatment of acute agitation. These choices usually consist of either the benzodiazepine lorazepam or a variety of antipsychotics, often administered in intramuscular (IM) form. Once the acute episode of agitation is appropriately managed, efforts at reducing the frequency and intensity of future episodes need to be considered.²

Goals for Acute Intervention

The initial goal for acute intervention (Slide 2) is to calm the patient.³ Intervening early in a patient’s episode of  agitation may prevent potential escalation from agitation to violence. In addition, calming the patient will allow diagnostic tests or procedures to take place. Ruling out a medical condition that could be the source of a change of behavior is vital, and physicians can begin to attenuate any present psychosis. By intervening early, physicians decrease the need for seclusion and restraint, thus reducing the risk of injury to the staff or patient.

Sleep is not a desirable outcome when treating a patient with acute agitation because it interferes with the evaluation. A sleeping patient will be unable to participate in treatment selection, may need assistance with toileting and hydration, and will consume more staff and nursing resources. The primary goal should be to calm the patient enough to continue on to treatment.

Pharmacologic Treatment   

Lorazepam

Until very recently, treatment options for agitation were limited to lorazepam and first-generation antipsychotics. Lorazepam, which has been in use for many years, leads to nonspecific sedation (Slide 3).³ Lorazepam’s  main advantage, in contrast to the other benzodiazepines, is that it is reliably absorbed intramuscularly. Lorazepam has a relatively short half-life of 10–20 hours, and has no active metabolites. The usual dose ranges from 0.5–2 mg, and can be administered every hour if necessary. It does not need to be administered intramuscularly; it can be given orally, sublingually, or intravenously.

Lorazepam is advantageous in that it treats any underlying alcohol or sedative withdrawal. This is especially important in a patient with an unknown medical history. Symptoms of alcohol withdrawal can emerge after a patient is admitted to the hospital. To a doctor who is unaware of a patient’s alcohol dependency, the agitation that accompanies alcohol withdrawal can be interpreted as a symptom of some other syndrome. Use of lorazepam can assuage both the patient’s agitation and withdrawal.

There are problems with lorazepam, however. Respiratory depression can occur in patients who are vulnerable to it, such as patients with chronic obstructive pulmonary disease, patients who are obese, or patients with a history of sleep apnea. It may also cause disinhibition or paradoxical reactions, which seem to cause patients to get more agitated and even aggressive. This latter complication is seen more often in patients who have some degree of brain damage. Though it is relatively uncommon, physicians should be alert to its possibility.

One drawback of using benzodiazepines such as lorazepam is that prolonged daily use is not optimal. Patients develop physiological tolerance and will require ever-increasing doses to achieve the same therapeutic effect. Lorazepam also has little to no effect on the core symptoms of psychosis.

First-Generation Antipsychotics

For decades, first-generation antipsychotics were the only alternative to lorazepam or barbiturates such as sodium amytal (Slide 4). Given a high enough dose, these agents universally cause sedation.⁴ Several intramuscular (IM) preparations are available. Clinicians can choose between the potency and sedating effects of agents. For example, chlorpromazine is a low potency/high sedating agent; haloperidol is a high potency/low sedating agent. In truth, both types can be used to quell agitation, but the risk of side effects varies with each. Hypotension, for example, is more commonly seen with chlorpromazine. Acute dystonia is more commonly expected with haloperidol.

An advantage of using first-generation antipsychotics is that they will treat underlying positive symptoms such as hallucinations and delusions in a patient with schizophrenia. First-generation antipsychotics and lorazepam are often combined. A popular combination is haloperidol and lorazepam, which can be administered in the same syringe. There are advantages in speed of onset and tolerability of this combination, but long-term use is still problematic. In addition to the problems associated with the prolonged use of lorazepam discussed above, the long-term use of first-generation antipsychotics can lead to problems with extrapyramidal side effects (EPS), such as acute dystonia (frightening for the patient and can lead to lack of future treatment adherence) or akathisia (often confused for agitation with resultant additional injections of the agent that caused the akathisia).

Droperidol, a neuroleptic approved by the Food and Drug Administration for use as a pre-anesthetic agent, is not approved to treat psychoses. Droperidol had been available in the United Kingtom, but was withdrawn from that market in 2001 because of the risk of QTc interval prolongation. A black box warning was consequently placed on the US product  label, and use of droperidol in the United States has declined. However, it is still considered to be a good sedating agent by many emergency room physicians. Droperidol can be given intramuscularly or intravenously, and can lead to a rapid reduction in agitation.

First-generation antipsychotics must be used with caution. As mentioned, these agents are associated with the occurrence of acute dystonic reactions and akathisia. If akathisia is mistaken for agitation, a clinician may decide to administer additional doses of first-generation antipsychotics, which will only compound the problem. Long-term exposure to first-generation antipsychotics has been associated with tardive dyskinesia. Additionally, a decrease in the seizure threshold can be seen with all first-generation antipsychotics, making patients who are withdrawing from alcohol or sedatives more prone to seizures.

Second-Generation Antipsychotics

Second-generation antipsychotics have been available for at least 10 years. They can be administered as regular capsules or tablets, liquid concentrates, orally disintegrating tablets, or IM formulations (Slide 5).⁴ IM formulations can be transitioned to oral dosing with good tolerability. One advantage of using the intramuscular second-generation antipsychotics for the treatment of acute agitation is their low rate of EPS, including akathisia. These medications will treat underlying psychoses, and there is evidence that they may treat more symptom domains in schizophrenia than just positive symptoms, for example negative symptoms, mood dysregulation, and cognitive dysfunction may be more effectively treated with a second-generation antipsychotic than with haloperidol.

The three available IM formulations of second-generation antipsychotics are ziprasidone, olanzapine, and aripiprazole. All three have been evaluated in registration studies in which the behavior of agitated patients was observed over time. The registration program for ziprasidone IM principally observed patients with schizophrenia; consequently, it is approved by the FDA only for the treatment of agitation associated with schizophrenia. The registration studies for olanzapine IM and aripiprazole IM studied patients with schizophrenia as well as patients with bipolar mania, and as a result the FDA-approved indications for those medications are agitation associated with schizophrenia and agitation associated with bipolar mania. All three of these second-generation antipsychotics decrease agitation and do so with a favorable EPS profile. Although there are no head-to-head comparisons of these three agents against each other, there are differences among them with regard to response rates, time to response, need for a second injection, and safety considerations.⁵

There are two available registration studies for ziprasidone IM. One study compared ziprasidone IM 20 mg to a ”pseudo-placebo” dose of 2 mg (Slide 6).⁶ Another compared ziprasidone IM 10 mg to 2 mg.⁷ Both the 10 mg and the 20 mg doses separated from the 2 mg “pseudo-placebo” dose, and after 2 hours there was substantial reduction in agitation, as measured by the Behavioral Assessment Rating Scale (BARS). The 20 mg dose showed a larger effect than the 10 mg dose, and although the product label states a range from 10–20 mg per injection, the optimal amount to use would be 20 mg.^6-8

Olanzapine IM was assessed in three registration studies.^9-11 Two involved patients with schizophrenia and one involved patients with bipolar mania. All three studies included a placebo control and an active control, and used the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) as the primary outcome measure representing agitation.^9-11 In both schizophrenia studies, haloperidol 7.5 mg was used as the active control. Lorazepam 2 mg was used as the active control for the bipolar mania study. In all three registration trials, olanzapine IM was superior to placebo. The single dose strength olanzapine IM study in agitated patients with schizophrenia demonstrated efficacy for olanzapine IM 10 mg as early as 15 minutes after injection (Slide 7).⁹ In the study comparing olanzapine IM, lorazepam IM, and placebo for bipolar mania and agitation, 10 mg of olanzapine IM was superior to both placebo and to 2 mg of lorazepam IM.¹¹

The product label recommends a dose of 10 mg, consistent with the results of the multiple dose study,¹⁰ and this is the usual dose administered. The dosage should be reduced in patients who are medically compromised or the elderly. In these cases, a dose of 2.5 mg or 5 mg would be more appropriate.

Aripiprazole is the most recently introduced second-generation antipsychotic available in a short-acting IM format. The efficacy of aripiprazole IM in the treatment of agitation was also assessed in double-blind randomized clinical trials comparing it to active controls of haloperidol and lorazepam, and using the PANSS-EC as the primary outcome measure.^8,12,13

The haloperidol active control was tested in patients diagnosed with schizophrenia, and the lorazepam active control was tested in patients diagnosed with bipolar mania. Aripiprazole IM separated from placebo in all three studies, and its time course was similar to those of the active controls.⁵ The recommended dose for aripiprazole IM is 9.75 mg (Slide 8).¹²

Safety Issues for Intramuscular Second-Generation Antipsychotics

The EPS profiles of these second-generation drugs are favorable to those of placebo or placebo-like controls, a significant advantage over the first-generation antipsychotics. A patient who experiences an acute dystonic reaction with a first-generation medication is unlikely to want to continue that treatment, fracturing his or her therapeutic alliance with the physician. According to the information contained in the FDA-approved product labeling, the rate of EPS events for ziprasidone was 2% for patients receiving 2 mg IM and 0% for those receiving 10 or 20 mg IM.¹⁴ Akathisia events were noted in 2% for patients receiving 10 mg IM and 0% for those receiving 2 mg or 20 mg IM.¹⁴ For olanzapine, any extrapyramidal event was noted for 0%, 4%, 2%, 0%, and 0% for patients receiving placebo, olanzapine 2.5 mg, 5 mg, 7.5 mg, and 10 mg IM, respectively, with corresponding rates of akathisia events of 0%, 2%, 0%, 0%, and 0%, respectively.¹⁵ For aripiprazole IM, the incidence of reported extrapyramidal events, excluding events related to akathisia, for aripiprazole IM treated patients was 2% versus 2% for placebo, and the incidence of akathisia-related events for aripiprazole IM treated patients was 2% versus 0% for placebo.¹⁶

Although risk of EPS is low for all three available IM second-generation antipsychotics, other risks should be considered. Product labeling for ziprasidone IM cautions that ziprasidone is contraindicated in patients with a known history of QT prolongation (including congenital long QT syndrome), with recent acute myocardial infarction, or with uncompensated heart failure. However, over 5 years’ clinical availability has not resulted in evidence that ziprasidone by itself poses a substantial clinical problem regarding QTc prolongation. Product labeling for olanzapine includes a caution regarding hypotension, bradycardia with or without hypotension, tachycardia, and syncope as reported during the clinical trials. Simultaneous injection of olanzapine intramuscular and parenteral benzodiazepines is not recommended. Similar to the warning for olanzapine, product labeling for aripiprazole notes include greater sedation and orthostatic hypotension with the combination of lorazepam and aripiprazole as compared to that observed with aripiprazole alone. 

Cost Differences Among Antipsychotics

The costs of ziprasidone, olanzapine, and aripiprazole are several-fold higher than the costs of lorazepam and haloperidol. However, the avoidance of acute dystonia and akathisia is priceless. These reactions require the administration of drugs such as benztropine  (the cost of benztropine IM 2 mg is $36.95 at Rockland Psychiatrists Center Pharmacy), and they extend the time a patient must spend in the emergency room. By avoiding dystonia and akathisia, one can obviate the need for benztropine or similar agents, and reduce the time spent in an emergency department, a patient’s resistance to taking antipsychotic medications, and both medication and non-medication costs.

Conclusion

In summary, our choices for management of acute agitation include environmental interventions and a selection of pharmacologic interventions. These latter treatments include the benzodiazepine lorazepam and an array of antipsychotic agents. The dominant choice of antipsychotic today would be one of the second-generation agents because of their superior tolerability profile in terms of EPS. Acute EPS, which can result from first-generation antipsychotic use, pose considerable challenges for a patient’s future treatment in terms of adherence, and iatrogenic worsening if akathisia develops. Once the acute episode of agitation is managed, longer-term approaches will need to be considered in order to reduce the frequency and intensity of future episodes of agitation. These longer-term strategies will need to appropriately balance the long-term efficacy and safety profiles of the agents in question.

References

1. Citrome L, Volavka J. Treatment of Violent Behavior. In: Tasman A, Lieberman J, Kay J, eds. Psychiatry. 2nd ed. John Wiley & Sons, Ltd; 2003:2136-2146.
2. Citrome L, Nolan KA, Volavka J. Science-based treatment of aggression and agitation. In Fishbein D, ed. The Science, Treatment, and Prevention of Antisocial Behaviors, Volume 2. Kingston, New Jersey: Civic Research Institute, Inc; 2004.
3. Citrome L, Volavka J. Clinical management of persistent aggressive behavior in schizophrenia: Part I Definitions, epidemiology, assessment, and acute treatment. Essent Psychopharmacol. 2002;5:1-16.
4. Citrome L. Atypical antipsychotics for acute agitation. New intramuscular options offer advantages. Postgrad Med. 2002;112(6):85-8, 94-96.
5. Citrome L. Intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: equipoise or not? J Clin Psychiatry. In press.
6. Daniel DG, Potkin SG, Reeves KR, et al. Intramuscular (IM) ziprasidone 20 mg is  effective in reducing acute agitation associated with psychosis: A double-blind,  randomized trial. Psychopharmacology (Berl). 2001;155:128-134.
7. Lesem MD, Zajecka JM, Swift RH, et al. Intramuscular ziprasidone, 2 mg versus 10 mg, in the short-term management of agitated psychotic patients. J Clin Psychiatry. 2001;62:12-18.
8. Tran-Johnson TK, Sack DA, Marcus RN, et al:  Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double- \blind, placebo-controlled trial. J Clin Psychiatry. 2007;68:111-119.
9. Wright P, Birkett M, David SR, et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry. 2001;158(7):1149-1151.
10. Breier A, Meehan K, Birkett M, et al. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002;59(5):441-448.
11. Meehan K, Zhang F, David S, et al. A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. J Clin Psychopharmacol. 2001;21:389–397.
12. Andrezina R, Josiassen RC, Marcus RN, et al. Intramuscular aripiprazole for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder: a double-blind, placebo-controlled comparison with intramuscular haloperidol. Psychopharmacology (Berl). 2006;188:281-292.
13. Zimbroff DL, Marcus RN, Manos G, et al. Management of acute agitation in  patients with bipolar disorder. Efficacy and safety of intramuscular aripiprazole. J Clin Psychopharmacol. 2007;27:171-176.
14. Geodon (ziprasidone HCl) capsules, Geodon (ziprasidone mesylate) for injection for IM use only. New York, NY: Pfizer; 2007.
15. Zyprexa (olanzapine) tablets, Zyprexa Zydis (olanzapine) orally disintegrating tablets, Zyprexa  IntraMuscular (olanzapine) for injection. Indianapolis, IN: Eli Lilly; 2006.
16. Abilify (aripiprazole) tablets, Abilify (aripiprazole) DiscMelt orally disintegrating tablets, Abilify (aripiprazole) oral solution, Abilify (aripiprazole) injection. Jacksonville, FL: Bristol-Myers Squibb; 2006. 

Question-and-Answer Session

Dr. Battaglia: The study of haloperidol and lorazepam you mentioned did not exclude patients without the ability to give informed consent.¹ The ziprasidone registration trials did have this exclusion criterion. If these studies exclude people who cannot give informed consent, is there a resulting bias in the degree of agitation being treated and in the outcome of these studies?

Dr. Citrome: The  haloperidol and lorazepam study was a randomized clinical trial, and informed consent was obtained whenever possible. In situations where patients were unable to give informed consent they were entered into the study based on the determination that rapid tranquilization was emergently indicated.¹ This is indeed different from all the registration studies we have discussed regarding not only ziprasidone, but also for olanzapine and aripiprazole, where all patients were required to provide informed consent.  You raise an important question: Are patients who enter studies where informed consent is required different from the patients we typically treat with these drugs? The answer, of course, is yes. A more disturbed patient has a lower likelihood of participating in, or being allowed to participate in, a randomized clinical trial, so these registration trials are biased toward moderately agitated patients who are more intact. We may not be able to generalize the outcomes of the registration trials to more disturbed patients.   

Dr. Robinson: You mentioned that the benzodiazepines might be more effective for agitation that is caused by hypnotic withdrawal or alcohol withdrawal. Besides that, are there any other predictors that can be used to select one class of agents over another?   

Dr. Citrome: We try to tease apart the causes of agitated and aggressive behavior in our research program. For patients whose agitation and aggression is attributable to psychosis, I would think that an antipsychotic would be more appropriate and more efficacious. But there are patients whose agitation and aggression are related more to impulsivity and poor frustration tolerance rather than active psychotic symptoms. For these patients, other agents may be considered, such as anticonvulsants, but the data supporting this is incomplete.

Dr. Robinson: Are there any studies on how to modify dosage ranges for elderly patients?   

Dr. Citrome: There was a study looking at 2.5 mg and 5 mg of olanzapine IM versus lorazepam IM 1 mg versus placebo IM  in patients with agitation associated with dementia.² The manufacturer ultimately did not pursue Food and Drug Administration approval for that indication, but the study gives us some information on how well this drug is tolerated among more medically compromised populations. Olanzapine was tolerated quite well among the patients in this study, all of whom were elderly. In terms of a general guide, I dose any of these agents at half, one third, or one quarter of the usual healthy adult dose for someone who is medically compromised.

Dr. Battaglia: For patients who are not in an acute emergency situation, how much impact does environment, such as hospital units, have on agitated behavior and treatment options?

Dr. Citrome: That is a wonderful question. In fact, we have made these kinds of observations on our specialized research unit.³ Our unit is a 24-bed inpatient unit at the Nathan S. Kline Institute for Psychiatric Research, operated in conjunction with Rockland Psychiatric Center, an intermediate and long-term care facility operated by the New York State Office of Mental Health. Twelve of our beds are in the part of the unit designed for patients with persistent impulsive and aggressive behavior. We have a series of video cameras to record events in the day room and courtyard where these aggressive patients often occur. We looked at the videotapes for a month in 2000 and a month in 2005, and counted up the aggressive incidents. We compared these with the incidents reported from rounds, incident reports, and progress notes. In 2000, we found that a large proportion of events were never recorded in the medical record but were observed in the video.

We then instituted a policy in which secure care therapy aids would report verbally aggressive and physically aggressive behaviors on a census sheet completed every half hour. That raised staff awareness of these behaviors. Consequently, 5 years later, the number of incidents was approximately the same, but the percentage of verbally aggressive incidents was higher and that of physically aggressive incidents was much lower. One possible explanation is that patients who were expressing verbal aggressivity were receiving interventions much sooner, and those incidents did not escalate. We also noticed that there were fewer unreported incidents in the written record. So by increasing our attention to these issues, increasing the awareness of staff, and increasing early interventions, we can reduce the progression of verbal aggression to physical aggression.

Early interventions can be as simple as talking with the patient and allowing them to ventilate, or it can involve the use of PRN medication.   

Dr. Ginsberg: Are there any studies of lorazepam combined with one of the second-generation agents? Is anything known of its cost efficiency or its clinical effects?

Dr. Citrome: As far as I know, there have been no controlled studies looking at combinations of second-generation antipsychotics in intramuscular form with benzodiazepines, but there is anecdotal experience. I think one has to be careful with this treatment strategy. Because of the risk of postural hypotension, the product labeling for olanzapine and for aripiprazole explicitly caution against combining with benzodiazepines. The product labeling for ziprasidone does not prohibit combination with lorazepam, but I probably would not. These medications should be potent enough to decrease agitation without combination. It may be cleaner to repeat a dose than to combine medications, which can create uncertainty about which drug achieved the dominant effect.

References

1. Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med. 1997;15:335-340.
2. Meehan KM, Wang H, David SR, et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: A double-blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology. 2002;26:494-504.
3. Nolan KA, Citrome LL, Saito K, Xu J. Reducing Inpatient Aggression: Paying Attention Pays Off. Poster Presented at: The 25th Congress of the Collegium International Neuropsychopharmacologicum; July 2006; Chicago, IL. Abstract in Int J Neuropsychopharmacol. 2006;9(Suppl 1):S150.