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.

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 all12.6 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, manicdepressive 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 6month 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

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 walkingassociated 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 drugseeking 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).

*
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 shortterm, 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 postelectroconvulsive
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 longterm 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 antiaggressive 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 disturbance
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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 5hydroxyindoleacetic 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, placebocontrolled, 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 placebocontrolled 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 placebocontrolled 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
15

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

16

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 cautionclonazepam, 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 patients 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
17

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.

18

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, obsessivecompulsive 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
19

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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