Aggression

Aggression and psychiatric disorders - Differential diagnosis and treatment approaches Most patients with mental disorders are not aggressive. Nonetheless, epidemiological evidence points to an increased risk for violence among individuals with a mental disorder compared to the general population. This article reviews this evidence and provides a framework for the assessment and treatment of these individuals.

Aggressive behavior in patients with psychiatric disorders has many possible causes. Probably the most important causes are the presence of comorbid substance abuse, dependence, and intoxication. In addition, the disease process itself may produce hallucinations and delusions, which may provoke violence. Often, poor impulse control related to neuropsychiatric deficits may facilitate the discharge of aggressive tendencies. Finally, underlying personality characteristics, such as antisocial personality traits, also may influence the use of violent acts as a means to achieve certain goals. Environmental factors that are associated with aggressive behavior include a chaotic or unstable home or hospital situation, which may encourage maladaptive aggressive behaviors. In the literature, terms such as aggression, violence, crime, and hostility are observed. Aggression is used for both humans and animals. In humans, aggression can denote verbal aggression, physical aggression against objects, or physical aggression against people. At times, aggression towards oneself (self-mutilation, suicidal gestures or acts) is included in the definition. Violence is used only when describing human behavior and denotes physical aggression by one person against another. Crime is defined as the intentional violation of criminal law. Hostility is a loosely defined term and can refer to aggression, irritability, suspicion, uncooperativeness, or jealousy.

This article mentions a number of medications. Full prescribing details, including precautions, adverse effects, use in pregnancy, and recommended dosing can be found in the manufacturer's product information sheet and is available in the Physicians' Desk Reference (PDR).

EPIDEMIOLOGY

The probability of violent behavior among patients with mental disorders is greater than that for the general population. Although patients with mental disorders do not commit most violent crimes, they are at increased risk for committing them. This especially is true for patients with mental disorders and substance abuse problems. The epidemiological studies supporting this statement have been conducted around the world and include a variety of cultures.

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In the United States, self-reports of violent behavior were obtained in the Epidemiological Catchment Area (ECA) project. The primary purpose of the project was to estimate the prevalence of untreated psychiatric disorders. Structured diagnostic interviews were administered to more than 20,000 persons residing in 5 areas of the country, both in the community and in institutions. In approximately 50% of this sample, data on violence were collected. The probabilities of violent behavior in male and female patients with schizophrenia were, respectively, 5.3 times and 5.9 times higher than in persons without any diagnosed mental disorder. The probabilities also were higher for patients diagnosed with affective disorder, but they were not higher for anxiety disorder. Patients with a mental disorder and a co-morbid substance abuse disorder had the highest probabilities of all—12.6 times higher for males and 9.1 times higher for females.

These results are supported by a smaller epidemiological study comparing 385 patients under (current or former) psychiatric care living in a community with 365 other residents who have never received psychiatric treatment. Self-reports of violent behaviors, ie, hitting someone, fighting, using a weapon, were, respectively, 2.4 times, 1.7 times, and 3.6 times more frequent in the patients than in the nonpatients. A US study made an attempt to compare rates of aggressive behavior among patients (N=1136) with comparable controls (N=519). Using self-reports collateral informants, and police and hospital records, the authors found no significant difference between the prevalence of violence by patients without symptoms of substance abuse (4.3%) and the community controls who also were free of symptoms of substance abuse (3.3%).

Substance abuse symptoms significantly increased the rate of violence to 14.1% of the patient sample and 11.1% of the controls. Moreover, the targets of patient violence were more likely to be family members, friends, or acquaintances (89.3%), rather than strangers (10.7%). The data are hampered somewhat by methodological questions, including the possibility of not accounting for patients who may be repeatedly assaultive and treatment-resistant and those who are lost to follow-up.

A number of studies have been performed using data from Scandinavian countries. In these countries, registries of hospitalizations, arrests, and incarcerations are available that include the entire population. A study of an unselected Swedish birth cohort (N=15,117) found that among persons without mental disorders, the conviction rate for violent offenses was 5.7% for men and 0.5% for women. Men with major mental disorders were approximately 4 times more likely to have been convicted of a violent offense than men without any mental disorder, and women with mental disorders were approximately 27 times more likely to be convicted than women without mental disorders. An even larger unselected cohort comprised of 324,401 Danes found that both men and women hospitalized at least once with major mental disorders (eg, schizophrenia, manic-depressive psychosis, psychogenic psychosis), mental retardation, antisocial

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personality disorder, drug use disorders, alcohol use disorders, and other mental disorders were morelikely to have been registered for at least 1 violent crime than persons with no history of psychiatric admissions. For the period 1978-1990, where computerized national police data were used in the analysis, men hospitalized with major mental disorders were approximately 9 times more likely to have been convicted of at least 1 violent offense than men with no history of psychiatric hospitalizations. For women, this relative risk was approximately 4.5.

A recent epidemiological study conducted in Finland found that among 11,017 people in one birth cohort, men who abused alcohol and were diagnosed with schizophrenia were found to be 25.2 (95% CI, 6.1-97.5) times more likely to commit violent crimes than men who are mentally healthy. Another Finnish study examining forensic patients (N=693) found that the risk of committing a homicide was about 10 times greater for patients with schizophrenia than it was for the general population. The risk increased to greater than 17 times for male patients with schizophrenia and coexisting alcoholism and greater than 80 times for female patients with schizophrenia and coexisting alcoholism. The actual number of positive cases in these large samples is small, however, and is dwarfed by the number of persons who were not mentally ill who commit violent crimes.

These findings are not limited to Scandinavia. Using case registries in Australia (N=4156), the odds ratio for violent offenses was 2.4 (P <0.001) for male individuals with schizophrenia with no substance abuse problems and 18.8 (P <0.001) for schizophrenia complicated by substance abuse. A review of data from 10 different countries reinforces the above findings. Using self-reports, other informants, and clinic or hospital records, the authors concluded that the occurrence rate of assault in the cohort of 1017 patients with schizophrenia was 20.6%, with the rate 3 times higher in developing countries (31.5%) compared with developed countries (10.5%). Thus, this issue is relevant internationally and transcends many cultures and environments.

The following discusses findings related to a causal relationship between psychosis and violence. Interviews of 121 incarcerated forensic patients who were psychotic (most with schizophrenia) examined the motives for the offenses committed while the patients were living in the community. Patients estimated that 82% of their offenses (violent and nonviolent offenses combined) were attributable to their illnesses. Delusions were the driving force for violent offenses among these patients. Note that this conclusion is somewhat weakened by the retrospective nature of the study.

Violent behavior in hospitals also has been studied. Violent or threatening behavior is a frequent reason for admission to a psychiatric inpatient facility, and that behavior may continue after the admission. During the first 24 hours after the admission to a psychiatric inpatient unit, 33 of 253 patients (13.0%) physically attacked another person. Patients who were manic were the most likely diagnostic group to be assaultive during the initial phase of hospitalization, with

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12 of 46 patients (26.1%) attacking another person, compared with 9 of 87 (10.3%) diagnosed with schizophrenia and 12 of 120 (10%) diagnosed with mental illness other than schizophrenia or mania. Another group reported that in the first 8 days after hospitalization, 25 of 289 patients who were schizophrenic or schizoaffective (8.7%) assaulted someone at least once.

Long-term hospitalization does not eliminate violent behavior. A study of 5164 long-term patients indicated that 7% of these patients physically attacked another person at least once during a 3-month period. Patients who were assaultive were more likely than patients who were nonassaultive to have a primary diagnosis of nonparanoid schizophrenia, psychotic organic brain syndrome, mental retardation, or personality disorder.

Many studies do not distinguish between recidivistic and transient assaultiveness, but such distinction is important. Persistent (recidivistic) and transient violence may differ in cause, management, and social consequences. A small number of patients may be responsible for the bulk of all incidents. This is supported by 2 studies. The first study, conducted in the United States, was a 6-month study of 1552 inpatients with various diagnoses that detected 576 violent incidents; a small group of recidivistic patients (5%) caused 53% of the incidents.

The diagnosis of schizophrenia was slightly overrepresented among the recidivists who were male; personality and impulse disorder diagnoses were frequent among the male and female recidivists. The second study was conducted in Australia. The patients who were recidivistic (12%) accounted for 69% of the 752 violent incidents identified. The males were more likely to have an organic brain syndrome, and the females were more likely to have a personality disorder.

ASSESSMENT AND DIFFERENTIAL DIAGNOSIS

Patient assessment

Patient assessment involves (1) the gathering of information about past and current behavior from the patient, health care providers, family, and friends; (2) a review of past treatment, (successful and unsuccessful); and (3) a clinical examination of the patient over time.

In the assessment of the patient who is acutely agitated and whose history is unknown, attempts are made to rule out somatic conditions that require emergency treatment. Delirium is a medical emergency. Once the patient is under behavioral control, further medical and psychiatric workups can be accomplished. Mechanical restraints may be necessary to prevent the patient who is agitated from injuring himself/herself or others while the medical workup is being conducted. For the patient who is acutely agitated and for whom the

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episode is one of many, the acute episode is managed, and, subsequently, time is devoted to strategies designed to reduce intensity and frequency of episodes. Included in a physical examination should be a thorough mental status examination. Key elements include an assessment of affect and thought content, especially hallucinations, delusions, suicidal ideation, and homicidal ideation. An assessment of orientation and memory also is crucial in establishing a differential diagnosis. Disorientation may be the first clue that an underlying somatic condition that is altering the mental status is present.

Care must be taken not to miss co-morbid conditions that may present with acute intoxication or withdrawal, such as alcohol or sedative abuse or dependence. Concomitant seizure disorder may complicate the clinical picture, especially if neuroleptic therapy appears to worsen the condition. Adverse drug effects, such as akathisia, may serve as a stimulus for striking out. Antisocial personality traits may be the most important factor in some instances of patient violence where goal-directed behavior, such as extortion of money or cigarettes, is evident.

Differential diagnosis

Differentiating patterns of violence central to the development of a differential diagnosis is the analysis of the pattern of the violence. Whether aggressive episodes are singular or repetitive, with low or high potential of actual injury, will guide the clinician in formulating immediate management plans, provisional diagnosis, and long-term strategy. Some patients are violent only when in a chaotic environment; others are persistently violent regardless of the milieu. Patients who were persistently violent were found to be more likely to have impairments in stereognosis, graphesthesia, tandem walk, and walking-associated movements and selective impairment in visual-spatial functioning found on neuropsychological testing. More detailed discussions regarding the neurology of aggression in general are beyond the scope of this chapter. In contrast to the patient who is persistently violent, those who are transiently violent respond to the introduction of a new structured environment.

Environmental factors leading to increased aggressive behavior in a psychiatric ward include crowding and, possibly, an over-authoritative attitude by nursing staff and underinvolvement of medical staff with regard to ward activities. Time of day may be a factor, with a peak problem period of 7:00-9:00 AM reported in one facility. Apparently, those who are transiently violent are more responsive to typical neuroleptic medication and have less neurological impairment than the patients who are persistently violent.

Schizophrenia Patients with schizophrenia living in the community usually would not fall into the persistently violent category, but they may present acutely with aggressive and violent behavior. This may be due to acute decompensation secondary to covert or overt noncompliance with psychotropic medication. Decompensation also may

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be due to a failure of the current medication regimen. The clinical features expected would be a worsening of psychotic symptoms and, possibly, command hallucinations, although the importance of the latter in violent behavior is in dispute. Studies report that 24-44% of aggressive acts committed by individuals with schizophrenia occur during an acute phase of the illness. Neuroleptic blood levels have been found to be inversely correlated with danger-related events in a group of recently hospitalized male patients who are schizophrenic.

Substance abuse, intoxication, and withdrawal Some of the violent behavior occurring among psychiatric patients is attributable to comorbidity with substance abuse. Aggressive and violent behavior in patients can be precipitated by alcohol, cocaine, phencyclidine (PCP), or amphetamine intoxication. Inpatients also can be abusing illicit substances because access to drugs and alcohol, although difficult, is not impossible. Caffeine intoxication, water intoxication, antihistamine intoxication, and the ingestion of deodorants and aerosols also have been described in inpatients. Withdrawal from substances can lead to aggressive behavior, sometimes in relation to goal-directed drug-seeking behavior and, at other times, in relation to paranoia and extreme anxiety.

Medical and neurological conditions Conditions such as brain injuries, brain tumors, or metabolic disturbances may precipitate aggressive behavior in a patient not normally known to be violent. For patients already in the hospital, regular and routine physical assessments, including laboratory tests, can be expected to screen for most problems. For patients with a history of seizure disorder, recent evidence suggests that interictal violence is associated more with psychopathology and mental retardation than with epileptiform activity or other seizure variables.

Dementia/Alzheimer disease Patients with dementia may be emotionally labile or prone to poor impulse control. Although some may appear frail, serious injury to self and others can result from a rage reaction to a perceived threat. Usually, a history of cognitive decline will clarify the diagnosis, but this history may not always be available in an emergency department. In the nursing home, the issue of behavioral dyscontrol has led to the use of mechanical and chemical restraints and has resulted in the development of federal regulations in the United States to curb their widespread use.

Antisocial personality disorders Antisocial personality disorders may coexist with other psychiatric disorders, including schizophrenia. Antisocial personality traits may be present even if the full disorder cannot be diagnosed. Violence secondary to the antisocial personality disorder/traits may be evaluated by examining the context of the aggressive incident. Intimidation of patients and staff or material gain may be factors in violent behavior. For example, fighting over money, cigarettes, and access to sexual partners and attacks on caregivers who deny a patient's request

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or try to set limits to patient behavior (such as enforcing a smoking ban) may occur.

Mood disorders Using a sample of 1140 recently incarcerated male felons, evidence was found of a direct relationship between a lifetime diagnosis of dysthymia and an arrest or incarceration history for robbery, as well as with multiple incidents of fighting since age 18 years. The manic state has been associated with violent behavior among 40 male psychiatric inpatients diagnosed with bipolar disorder. In a sample of 20 inpatients with mania and 856 with other diagnoses, assaultiveness was not present in the manic group, but agitation was observed more frequently when compared to all other diagnostic categories.

Anxiety disorders Posttraumatic stress disorder (PTSD) has been associated with anger, hostility, and violence, although the presence of co-morbid conditions, such as mood disorders and substance abuse disorders, may be confounding factors. These confounding factors were controlled for in a study of 27 outpatients who were Vietnam veterans with PTSD and 15 controls who were Vietnam combat veterans without PTSD. Subjects with PTSD scored significantly higher than subjects without PTSD on measures of hostility and violence.

Panic disorder with aggressive thoughts and behaviors in association with panic symptoms has been reported in a series of 3 patients. Although each patient was interviewed carefully using standard diagnostic criteria, the case descriptions hint at significant disturbances of mood and impulse control, the presence of substance abuse, and a history of trauma. TREATMENT - MANAGEMENT OF ACUTE AGGRESSION

A number of books and articles offer good practical advice on handling patients who are agitated and on training issues. Others focus on restraint and seclusion and on psychodynamic strategies. Behavioral, psychological, and pharmacological interventions are used simultaneously. Organizations, such as Non-Abusive Psychological and Physical Intervention, Inc (NAPPI), are available to train hospital and clinic staff in methods of assessing, preventing, and physically managing dangerous behavior. Typically, the staff is trained as a team and includes physicians, nurses, therapy aides, social workers, psychologists, security personnel, and others who might have patient contact. The principal elements of the non-pharmacological management of aggressive behavior include the following:

* Assess the environment for potential dangers (objects that can be thrown or used as a weapon).

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* Assess the physical demeanor of the patient (for example, many patients will make a fist before punching or kicking).

* Know where the patient is at all times (do not turn your back to the patient).

* Take verbal threats seriously.

* Remain several feet away from the patient to avoid crowding the patient.

* Clear the area of other patients.

* Remain calm and maintain a confident and competent demeanor and attempt to de-escalate by engaging the patient in conversation.

* Avoid arguments between staff members in front of the patient.

* If restraints are necessary, have at least 4 people available.

No specific pharmacological treatment for violent or aggressive behavior exists; however, nonspecific sedation often is used in the management of a patient who is acutely agitated. In general, intramuscular injection of a sedative has a faster onset of action than oral administration, but a patient may calm down readily after an oral dose because the patient realizes that action has been taken and help is being provided. Sublingual administration may have a faster onset of action than oral ingestion and has the added advantage of distracting the agitated patient while the pill is dissolving.

Lorazepam Lorazepam appears to be a good rational choice when treating an acute episode of agitation, especially when the etiology is not clear. Lorazepam is a nonspecific sedating benzodiazepine. A brief but influential report compared the antiaggressive effects of a single dose of haloperidol (10 mg) with a single dose of lorazepam (2 mg) in violent psychiatric patients at a crisis unit. Lorazepam was at least as effective as haloperidol in controlling violent behavior. Of all the benzodiazepines available, lorazepam is the only one reliably absorbed when administered intramuscularly. Its half-life is relatively short (10-20 h), and it has no active metabolites. The usual dosage of 0.5-2.0 mg every 1-6 hours may be administered orally, sublingually, intramuscularly, or intravenously. Caution is required when respiratory depression is a possibility, but this is less of a problem than with sodium Amytal, an agent popular before the advent of lorazepam. Reports have been made of an interaction of benzodiazepines with clozapine, producing (sometimes fatal) respiratory depression and marked sedation, excessive sialorrhea, and ataxia, but this combination has been used successfully by a number of practitioners. Paradoxical reactions to benzodiazepines, as exhibited by hostility or violence, have been an area of

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concern, but the evidence is not convincing. Disinhibition with benzodiazepines is, in any event, uncommon and even more unlikely to occur when benzodiazepines are administered within the context of single or limited doses in a crisis situation. In current clinical practice, long-term control of violence with benzodiazepines is not used widely due to practical and ethical problems with tolerance and dependence. However, lorazepam is an excellent tool for short-term, quick reduction of violent behavior. The possibility of alcohol or sedative withdrawal as a cause of agitation is another point in favor of using lorazepam. The use of a neuroleptic in this instance is suboptimal and may lower the seizure threshold. If delirium tremens is present, full supportive medical care must be available; when medical complications arise, the mortality rate has been reported as high as 20%.

Haloperidol Neuroleptics universally cause sedation when administered at a high enough dose. Haloperidol, a butyrophenone, has been used frequently as an intramuscular medication as needed for agitation and aggressive behavior, including in an emergency department setting, for a wide variety of patients. The advantage of haloperidol over the low-potency neuroleptics (eg, chlorpromazine) is that it causes less hypotension, has fewer anticholinergic adverse effects, and causes less of a decrease in the seizure threshold. Despite the advantages of haloperidol over chlorpromazine, clinicians may desire a more sedating agent, so the low-potency neuroleptics continue to be used. In addition to this nonspecific sedation, a benefit would be its antipsychotic effect, but this would be evident only after the acute episode of agitation has subsided. Although once popular, rapid tranquilization with injectable haloperidol does not lead to a more extensive or rapid alleviation of psychotic symptoms, as observed in a group of patients who are mainly schizophrenic.

Neuroleptics may have a longer-lasting effect on the reduction of agitation by treating the underlying psychosis. On the other hand, high doses of neuroleptics may lead to more adverse effects, including akathisia. Akathisia increases irritability and has been reported to be associated with violence in several cases. High-dose haloperidol treatment of chronic schizophrenia (60 mg/d) has been associated with violence; akathisia might have been the mediating variable. For patients who are resistant to typical neuroleptics, no benefits exist beyond the acute sedative effect.

Acute mania, frequently associated with assaultiveness, can be controlled effectively and quickly by antipsychotics. Low doses of haloperidol or other neuroleptics are used to manage aggression in elderly patients. Neuroleptics are prescribed frequently to reduce aggressive behavior in persons with mental retardation, but their effectiveness for this indication is doubtful. Small studies of various neuroleptics reported some success, but a large placebo-controlled study has demonstrated a significant (but unexplained) increase of aggressiveness with thioridazine (200 mg/d). These investigators suggested that the removal of

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physical restraints resulted in a decrease of aggressiveness that was independent of psychopharmacological treatment. The administration of neuroleptics to control behavior of individuals who are nonpsychotic and who are mentally retarded is common, but the effectiveness and safety of this treatment have not been demonstrated clearly, and the practice remains controversial. Haloperidol was used successfully in a sample of 11 patients who developed violent, aggressive behavior after a severe closed head injury.

Droperidol Droperidol, another neuroleptic in the butyrophenone class, is used most often for induction of anesthesia. The medication is not approved by the Food and Drug Administration (FDA) for psychiatric conditions but has been used for sedating agitated patients in an emergency department setting. A case report of coma following intravenous droperidol administered for post–electroconvulsive therapy (ECT) delirium is cautionary, and adequate medical backup and the availability of intubation and oxygen is urged. Thus, droperidol should not be used in psychiatric hospitals where such backup is not immediately available.

Atypical antipsychotics The new atypical antipsychotics may emerge as important options in the management of acute agitation in psychosis. Although sedation remains the primary mode of action when used emergently in patients who are acutely agitated, the atypical antipsychotics have several advantages over typical antipsychotics. These advantages include a lower propensity for extrapyramidal adverse effects (including akathisia), a lower propensity towards tardive dyskinesia, and, perhaps, a specific antiaggressive effect over time, as will be described later. A current limitation is the lack of FDA-approved intramuscular preparations of atypical antipsychotics. This may change upon the possible approval of ziprasidone. Intramuscular ziprasidone has been studied in phase III clinical trials in patients who are acutely agitated and has demonstrated some success in reducing the symptoms of agitation with no or little resultant dystonia or akathisia.

Antipsychotics - A caveat Using antipsychotic agents for aggressive patients who are non-psychotic generally is not recommended. Nonspecific sedating agents, such as lorazepam, would be preferable. The use of antipsychotics places the patient at risk for adverse effects, such as dystonia or tardive dyskinesia in the longer term. Moreover, that antipsychotic-induced akathisia can result in further agitation cannot be overemphasized. Although the newer atypical antipsychotics have a lower propensity to cause these adverse effects, the risk is not eliminated.

Acute aggressive behavior In summary, patients with aggressive behavior first must be assessed for the possibility of comorbid conditions. Medical conditions, including acute withdrawal from alcohol or sedatives, should be ruled out. Beyond the acute management of

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an aggressive episode, long-term management depends on the pattern of violence, either transient or persistent.

Short-term sedation with lorazepam is a safe and effective choice for the acute episode. Use of neuroleptics may lead to adverse effects, such as akathisia, which may in turn precipitate further agitation.

THE NEXT STEP AFTER THE ACUTE AGGRESSIVE EPISODE

Once the acute agitation is managed, longer-term strategies are required. As useful as lorazepam is as an acute intervention, it is not recommended as a long-term solution. Specialized units, such as secure or psychiatric intensive care units, provide a structured environment that optimizes staff and patient safety. In general, these specialized units are staffed with persons trained in interacting with patients who are volatile and difficult to manage. Preventive aggression devices (PADS) are a form of ambulatory restraints that can be used as an alternative to seclusion. Patients in these wrist-to-belt and/or ankle-to-ankle restraints can remain with their peers on the ward, eat their meals, and interact yet are prevented from striking out and injuring others. When used in combination with a comprehensive behavior modification program, these patients can be weaned off of the ambulatory restraints.

Pharmacotherapy for the longer-term management of violent behavior depends on the individual patient's underlying clinical problem. Theoretical rationales for treatment strategies have included the serotonin hypothesis. The atypical antipsychotics (eg, clozapine, risperidone), beta-adrenergic blockers, mood stabilizers (eg, lithium, carbamazepine, valproate), antidepressants, and buspirone have been used.

Treatment of the underlying disorder is key. Often, when the primary psychiatric problem is treated successfully, the associated aggressive behavior is reduced. Unfortunately, perhaps one third of patients with schizophrenia do not respond to antipsychotic treatment or respond only partially. Chronically violent patients with schizophrenia may receive higher doses of neuroleptics without clear evidence that this reduces the incidence of violent behavior. This actually may worsen akathisia, further increasing the risk of aggressive behavior, as discussed earlier.

Other complicating factors are co-morbid conditions, such as substance abuse or antisocial personality disorder. Because of the above considerations, several pharmacological agents have been studied with regard to specific anti-aggressive activity, the goal being to utilize them to target aggressive behavior specifically.

A common theme among many agents proposed as anti-aggressive drugs is their effect on the serotonin neurotransmitter system. The serotonergic system is involved in the modulation of aggressive behavior in many species. A

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disturbance of this system has been implicated in impulsive violence in humans. Impulsive violent behavior may be directed against others or against oneself.

These issues have been reviewed extensively elsewhere. In humans, disturbance of the serotonergic system has been inferred from low levels of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) or from a blunted response to neuroendocrine challenges. This work was conducted largely with aggressive patients with personality disorders and substance use disorders. Drugs that affect the serotonin neurotransmitter system include antipsychotics (eg, clozapine, risperidone), antidepressants (eg, fluoxetine, citalopram), and anxiolytics (eg, buspirone). These and other medications are described in the following sections.

Special mention should be made of the legal implications of treating a patient who has aggressive behavior, specifically regarding any threats this person may make towards somebody else. Extensive debate has occurred regarding the duty to warn and the duty to protect (the most famous case being that of Tarasoff). In these matters, the issue of patient confidentiality may be overruled by safety concerns. Although discussion of these issues is beyond the scope of this chapter, the clinician must be mindful of any specific threat a patient may make. Hospitalization of the patient may satisfy the immediate need to protect a potential victim, but further consultation is highly recommended.

ANTIPSYCHOTICS FOR PERSISTENT AGGRESSIVE BEHAVIOR

Clozapine The atypical antipsychotic clozapine, in addition to being an effective treatment in patients refractory to typical neuroleptics, may have specific anti-aggressive effects. This may be due to the effects of clozapine on the serotonin system, as well as its selective affinity for the limbic system. One retrospective study in a state hospital found that the number of violent episodes among inpatients with schizophrenia decreased after they began clozapine treatment. Similar results were found among 5 patients with schizophrenia in a specialized unit for severely aggressive patients and also in 2 of 8 patients with brain injuries who exhibited chronic posttraumatic aggressive behavior.

In a program spanning 21 state hospitals in New York, 223 patients with schizophrenia who received clozapine had the Brief Psychiatric Rating Scale completed at baseline, 6 weeks, 12 weeks, and at the end point. A selective effect of clozapine on hostility was found. Another study reported a reduction in the use of seclusion and restraints in a group of patients in a state hospital who were schizophrenic and schizoaffective who received clozapine.

Although no controlled studies of the anti-aggressive effects of clozapine are available, the preponderance of evidence indicates that this drug reduces aggressive behavior in those with schizophrenia and schizoaffective disorder.

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These effects cannot be fully explained by sedation or by general antipsychotic effects.

Risperidone The atypical neuroleptic risperidone also affects the serotonin system and has been demonstrated to have a selective effect on hostility, as well. The authors had access to the database generated by a multi-center, double-blind, placebo-controlled, parallel group, 9-week clinical trial of risperidone versus haloperidol. Hostility was measured by the Positive and Negative Syndrome Scale. One

hundred thirty-nine patients had a baseline hostility score of at least mild, and all carried the diagnosis of schizophrenia. Risperidone was found to have a greater selective effect on hostility than did haloperidol. This effect will need to be compared with that of clozapine. Such studies currently are under way.

BETA-BLOCKERS AND MOOD STABILIZERS FOR TREATMENT OF PERSISTENT AGGRESSION

Beta-blockers

Beta-adrenergic blockers, in particular propranolol, have been used in the treatment of aggressive behavior. Several propranolol trials have been published regarding patients with organic brain disease. Subject age ranged from 7-86 years. The diagnoses included mental retardation; autism; posttraumatic organic brain syndromes; various types of dementia; Huntington disease; Wilson disease; post-encephalitic psychosis; and apparent or presumed chronic central nervous system dysfunction inferred from soft neurological signs, abnormal findings on EEG, or clinical seizures.

The time of onset of the anti-aggressive effect of propranolol is difficult to glean from the reports; it appeared to range from 12 hours to 2 months. Current literature suggests that onset of the anti-aggressive effects can be observed 4-8 weeks after the effective dose is reached. The effective doses can be reached only after a gradual buildup. The dose of propranolol perceived as effective by the researchers was remarkably variable. Doses higher than 600 mg/d are used only exceptionally. The dose-response relationship has not been studied systematically.

Propranolol has been used as an adjunctive treatment for schizophrenia, and a reduction in symptoms, including aggression, was found. A chart review of chronically assaultive patients with schizophrenia receiving nadolol or propranolol revealed a 70% decrease in actual assaults for 4 of the 7 patients. A double-blind placebo-controlled study of adjunctive nadolol in 41 patients, 29 of whom were schizophrenic, found a decline in the frequency of aggression compared with controls.

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Another double-blind placebo-controlled study of adjunctive nadolol in 30 violent inpatients, of whom 23 were schizophrenic, found a trend towards lower hostility for the active treatment group. Both nadolol studies involved dosages of as much as 120 mg/d. Nadolol was as effective as propranolol in suppressing aggressive behavior in a patient who was retarded who received a separate trial of each of these 2 agents. Metoprolol, a selective beta-adrenergic receptor blocker, was effective in 2 cases of intermittent explosive disorder and 2 cases of mental retardation.

The main practical problem with the administration of propranolol for aggression is the high frequency of cardiovascular adverse effects (reduction of pulse rate and blood pressure). Pindolol, besides its nonselective beta-adrenergic blocking activity, has a partial agonist effect (intrinsic sympathomimetic activity). This accounts for a reduction of cardiovascular adverse effects of pindolol in the normotensive population, making it a safer and more attractive compound for psychiatric indications than propranolol. Pindolol was tested in a double-blind placebo-controlled crossover study using 11 patients with dementias of varying origin. It reduced assaultiveness and hostility without producing lethargy.

Mood stabilizers

Mood stabilizers, such as lithium, valproate, and carbamazepine, are used as the primary medication treatment for bipolar disorder and as adjuncts to neuroleptic treatment for patients with schizophrenia. Although they are not prototypical antiaggressive drugs, they commonly are used for this purpose in clinical practice. A survey of a state psychiatric hospital in New York revealed that 25% of the patients were receiving lithium, carbamazepine, or valproate. Diagnoses were schizoaffective disorder (44%), schizophrenia (28%), bipolar disorder (19%), or other diagnoses (9%). The indications for the mood stabilizers, as documented in the clinical records, were impulse control (46%), assaultive or aggressive behavior (44%), or other indications (10%). The adjunctive use of mood stabilizers (especially valproate) in schizophrenia has increased markedly in the past 5 years.

Lithium Aggressivity is observed frequently during manic episodes. Reduction of aggressivity is an important part of the therapeutic effect of lithium in patients who are manic. The anti-aggressive properties of lithium in people who are mentally retarded were first demonstrated in an open study in 1970 that demonstrated that the effect of this treatment was not limited specifically to aggressive behavior; additional reductions of restlessness and hyperactivity occurred.

The anti-aggressive effects of lithium in people who are mentally retarded were confirmed in another open trial in 1984, a retrospective study in 1989, and in a double-blind placebo-controlled trial in 1987. The recommended serum lithium

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concentration for anti-aggressive effect was 0.7-1.0 mEq/L or 0.5-0.8 mEq/L. Although the original report mentioned uncontrollable polydipsia and enuresis, these adverse effects of lithium treatment were not prominent in the placebo-controlled larger trial or in the other open study using slightly lower lithium serum levels.

A small retrospective uncontrolled study confirmed the anti-aggressive effects of lithium in patients who were mentally retarded; self-injurious behavior exhibited by these aggressive individuals also was reduced by the treatment. Belligerence in a patient recovering from a head injury failed to respond to propranolol or haloperidol, but it disappeared when the patient was administered lithium; the effective levels were 0.4-0.8 mEq/L. Maintaining the plasma levels relatively low may be important because a severe closed head injury was reported to reduce tolerance to lithium neurocognitive adverse effects in a patient who was bipolar and maintained on lithium.

Lithium treatment reduced the number of infractions involving violent behavior of recurrently violent prisoners in open trials, as well as in a double-blind placebo-controlled study. Lithium plasma levels in these trials were mostly below 1.0 mEq/L; such relatively low levels generally are not associated with lethargy or general suppression of motor activity in adult patients. Most prisoners in the open trial had various organic mental syndromes or schizophrenia, whereas the subjects in the controlled trial were described as having nonpsychotic personality disorders.

A paradoxical increase of aggressivity during lithium treatment has been described. This patient had a temporal lobe EEG spike focus. His abnormality on EEG and aggressivity increased simultaneously after the start of lithium treatment and then improved after the treatment was stopped. However, a study reporting beneficial effects of lithium included at least 4 patients with epilepsy (1 had temporal lobe epilepsy) and another study observed 8 patients with epilepsy, only 1 of whom demonstrated a slight increase of seizure frequency during the lithium treatment.

The effectiveness of lithium therapy in schizophrenia is not established. Active affective symptoms, previous affective episodes, and a family history of affective disorder may predict a favorable response to lithium but also may provide clues that the diagnosis could be something other than schizophrenia. A double-blind, placebo-controlled, parallel-design clinical trial involving seriously ill state hospital patients with schizophrenia who had not responded to prior trials of typical neuroleptics demonstrated no advantage of lithium combined with haloperidol over haloperidol alone.

When lithium was added to neuroleptics for the treatment of patients with resistant schizophrenia who were classified as dangerous, violent, or criminal, no benefits were observed after 4 weeks of adjunctive lithium. However, case

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reports mention patients with paranoid schizophrenia with aggressive or disorderly behaviors who have responded to the addition of lithium to their neuroleptic treatment and who deteriorated after the lithium was discontinued but who subsequently improved when it was reinstituted.

Valproate Valproate for the control of aggressivity has been described to date in approximately 20 published reports comprising approximately 200 patients. Diagnoses in these reports cover the spectrum of psychiatric conditions, including dementia, borderline personality disorder, organic mood syndrome, bipolar disorder, schizophrenia, mental retardation, and schizoaffective disorder. Methodology of these studies included case reports, retrospective chart reviews, and open-label designs. Only one double-blind study has been reported, in which 16 patients with borderline personality disorder were enrolled and improvement was noted.

A comparison of valproate and carbamazepine in hospitalized patients (diagnosis not reported) revealed a decrease in the number of hours spent in mechanical restraints for both groups, with valproic acid being more effective than carbamazepine. An open design study involving 35 individuals randomly selected from consecutive admissions to a large state hospital setting found that divalproex sodium reduced agitation in patients with bipolar disorder or borderline personality disorder, as measured by the number of hours spent in seclusion per week. Although commonly used in patients with schizophrenia, valproate has not been studied adequately in this population.

Carbamazepine Studies examining the usefulness of carbamazepine in the control of aggressive behavior are few. Eight women diagnosed with schizophrenia (some with EEG abnormalities) and exhibiting violent behavior were administered carbamazepine in addition to their regular neuroleptic medication, with good results. In a retrospective study of violent patients, mostly with schizophrenia and with and without abnormalities on the EEG, significant reductions in aggressivity were noted with carbamazepine, regardless of EEG status. A brief letter reported that carbamazepine was administered in an open uncontrolled trial to 34 adult inpatients with rage outbursts of various etiologies. Most patients (N=19) had intermittent explosive disorder. Significant improvement was noted in the severity of physical assaults.

A multi-facility double-blind study comparing the effect of a 4-week trial of adjunctive carbamazepine versus placebo with standard neuroleptic treatment was conducted on 162 patients with a DSM-III diagnosis of schizophrenia or schizoaffective disorder, all with excited states or aggressive/violent behavior that responded unsatisfactorily to neuroleptic treatment. No statistically significant difference in response occurred among the patients receiving either adjunctive

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carbamazepine or placebo, but a trend towards moderate improvement with carbamazepine was noted (P <0.10).

A 15-week, double-blind, randomized within-patient crossover study assessing adjunctive carbamazepine in chronic inpatients without epilepsy and with EEG temporal lobe abnormalities was performed on 13 patients, 9 of whom had schizophrenia and of whom 7 completed the study. Overt aggression was rated as twice as severe and 1.5 times as common on placebo compared with carbamazepine. Response was not correlated with EEG deterioration or improvement.

With rare exceptions, the published studies of carbamazepine and aggressivity are not blinded and are uncontrolled for placebo effect. In addition, plasma levels of concomitant neuroleptics are not measured, leaving open the possibility for undetected pharmacokinetic interactions. Despite these limitations, carbamazepine does appear to be a useful adjunct to neuroleptic therapy and may lower aggression in a broad spectrum of disorders.

Thus, the available evidence indicates that mood stabilizers may reduce aggressive behavior in patients with a broad spectrum of diagnoses. Mechanisms of the antiaggressive action of mood stabilizers are unclear. Because most of the reported trials used mood stabilizers as adjunctive treatment, some of the effects possibly depend on pharmacodynamic and pharmacokinetic interactions with antipsychotics or other concomitant medications.

OTHER AGENTS AND CONCLUSION

Benzodiazepines

Clonazepam A word of caution—clonazepam, a high-potency benzodiazepine, had been reported to be useful as an antiaggressive agent in a case report of a patient with schizophrenia and a seizure disorder. In this particular case, both phenytoin and carbamazepine were ineffective treatment. The patient’s treatment was most successful with a combination of haloperidol and clonazepam. This result is in contrast to a double-blind placebo-controlled trial of adjunctive clonazepam in 13 patients with schizophrenia who were receiving neuroleptics. In that study, no additional therapeutic benefit was observed, and, in fact, 4 patients demonstrated violent behavior during the course of clonazepam treatment.

Antidepressants

Amitriptyline The value of amitriptyline for the treatment of posttraumatic agitation (including some threatening behavior) was observed in a case report of a patient who

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developed agitated, physically threatening behavior after a closed head injury; this behavior was witnessed in additional patients. The current interest in the role of certain antidepressants in aggression is based on the crucial role of serotonergic regulation of impulsive aggression against self and others. Antidepressants with specific effects on serotonin (5-HT) receptors are available now.

Trazodone Trazodone, a selective 5-HT2 antagonist, reduced violent outbursts in an open trial of 4 patients with dementia who showed no clinical signs of depression; these observations were partially replicated in another sample of 7 patients with dementia who were aggressive, 3 of whom improved. A combination of trazodone and tryptophan (a serotonin precursor) was used successfully to reduce aggressive behavior and temper tantrums in a patient who was mentally retarded and in several elderly patients who were demented. A similar effect was reported in an adult patient with Down syndrome when trazodone was administered in combination with a serotonin-enhancing diet.

Fluoxetine Fluoxetine, a selective serotonin reuptake inhibitor, decreased impulsive aggression (including assaultiveness) in 3 patients with personality disorders; this was an open trial. Patients with chronic schizophrenia who remained symptomatic while maintained on antipsychotics were administered adjunctive fluoxetine; violent incidents decreased in 4 cases and increased in 1 case in this retrospective uncontrolled study. Fluoxetine was effective against anger attacks in patients with unipolar depression who were irritable and hostile. A study of 21 persons who were severely to profoundly mentally retarded and who also displayed aggression and self-injurious behavior and were treated with fluoxetine on an open-label basis demonstrated a positive outcome for 19 of the subjects; no worsening attributable to fluoxetine was reported for the remaining 2 patients. In a preliminary medication trial with 5 patients with refractory borderline disorder, fluoxetine led to a decrease in impulsiveness.

Fluoxetine has been blamed for inducing murder or suicide and has been used as a legal defense and as a plaintiff's argument in seeking compensatory and punitive damages in a variety of court cases. In early 1990, a case report examined 6 patients who were depressed but free of recent serious suicidal ideation who developed intense and violent suicidal preoccupation after starting fluoxetine treatment. The authors recommended that fluoxetine be used cautiously. In another study, increased aggression was observed in a group of 19 adult inpatients who were mentally retarded and had epilepsy and a history of current or recent aggressive behavior. Each was taking other psychotropic medication concurrently, with wide individual differences in fluoxetine drug response.

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The Lilly research laboratories have published several meta-analyses concluding that fluoxetine is not associated with increased suicidality in treatment for obsessive-compulsive disorder, increased suicidality during pharmacotherapy for depression, or increased aggression. Specifically, a relative risk analysis of 3992 subjects enrolled in several double-blind placebo-controlled clinical trials covering multiple indications (eg, depression, obesity, bulimia nervosa, obsessive-compulsive disorder, smoking cessation, alcoholism) demonstrated a 4-fold higher likelihood for an aggressive event for patients receiving placebo compared with fluoxetine. A thoughtful review and reinterpretation of the emergence of suicidal and aggressive behavior during antidepressant treatment places this clinical issue in perspective.

Citalopram The antidepressant citalopram, a selective serotonin reuptake inhibitor newly available in the United States, was tested for antiaggressive effects in 15 patients who were chronically violent and hospitalized with schizophrenia. This was a double-blind placebo-controlled crossover study that lasted 48 weeks (24 wk on active citalopram, 24 wk on citalopram placebo). The trial medication was added to the concurrent neuroleptic treatment. The number of aggressive incidents decreased during the active citalopram treatment.

Anxiolytics

Buspirone Buspirone, an anxiolytic with antidepressant properties and a 5-HT1A receptor agonist, was reported to improve aggressive and self-injurious behavior in 9 of 14 patients who were mentally retarded; this effect was confirmed in a controlled study by the same group. Several case studies reporting similar results were published. A case of posttraumatic belligerence (patient described as "extremely hostile, argumentative, impulsive, and threatening") was successfully managed with buspirone, which was started several months after the head injury.

Conclusion

Treatment of the underlying psychiatric disorder is essential to reducing violence. A careful assessment, leading to correct diagnosis, will optimize treatment selection. Clozapine appears to be more effective than typical neuroleptics in reducing aggressivity in patients with schizophrenia or schizoaffective disorder. Risperidone also appears promising in reducing hostility. Both of these agents appear to have selective antiaggressive activity in addition to their antipsychotic properties, making them particularly suitable for patients who are both aggressive and have schizophrenia.

Beta-blockers, well studied in the treatment of aggressive behavior in patients with brain injury, also may be helpful as an adjunctive agent to neuroleptics for aggression and schizophrenia. Mood stabilizers, such as carbamazepine and

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valproate, also are used with patients with schizophrenia, typically as an adjunct to neuroleptic treatment to decrease the intensity and frequency of agitation and poor impulse control. However, they have not been extensively studied under double-blind placebo-controlled conditions.

Lithium certainly is useful as an anti-manic medication and will reduce agitation and aggression in patients with bipolar disorder. Lithium has been reported as being useful in reducing aggression in people who are mentally retarded, as well as reducing the number of infractions involving violent behavior in a study of prisoners who are recurrently violent. The use of lithium for schizophrenia and aggression has not been investigated adequately.

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This Test

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