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Introduction
Violent behavior associated with mental disorders is a common reason for admission to a psychiatric inpatient unit. Once hospitalized, patients may continue to be intermittently agitated and have persistent aggressive behaviors, preventing their discharge back into the community.
The pharmacological management of agitated, aggressive, and violent behavior can be conceptualized as having two parts: acute and preventative. Acute treatment options are plentiful and generally efficacious. Preventative treatment aims to decrease the frequency and intensity of future acute episodes of agitated, aggressive, and violent behavior, and although effective therapeutic options do exist, they are far from being “one size fits all,” and are highly dependent on the root causes of the dangerous behaviors. With few exceptions, most of the clinically relevant research in the longer-term management of violence has been conducted in psychotic individuals with schizophrenia.
Definitions and Scales
Agitation (excessive motor or verbal activity) can further escalate into aggressive behavior. Agitation can be associated with a number of conditions, including schizophrenia and bipolar disorder. Acute agitation in its severest forms is a medical emergency that requires immediate intervention to alleviate personal distress and to prevent harm to the individual and/or others.
Specific rating scales have been developed to measure agitation, such as the single-item Behavioral Activity Rating Scale (BARS) [1]. Also commonly used in the development of anti-agitation agents is the Positive and Negative Syndrome Scale (PANSS) Excited Component (EC), or “PEC,” which consists of the five PANSS items considered relevant in this regard: excitement, hostility, tension, uncooperativeness, and poor impulse control [2]. The PEC and BARS have been successfully used as the primary outcome measures to garner regulatory approval for several agents for the indication of agitation associated with schizophrenia and/or bipolar mania.
Aggressive behaviors can be verbal, against objects, against self, or against other persons. Physical aggression against other persons is frequently called violence. Aggressive behaviors have been assessed in research using questionnaires such as the Overt Aggression Scale (OAS) [3]. In clinical settings with acutely ill psychiatric patients, the Brøset Violence Checklist (BVC) can be used to predict inpatient violence in the short-term [4]; this instrument assesses the presence or absence of behaviors or states frequently observed before a violent incident, including confusion/disorientation, irritability, and threats. The goal of longer-term treatment is to minimize the future occurrence of aggressive behaviors. There are no agents specifically approved for aggression or violence per se. However, there is a substantial body of research examining these longer-term treatment options.
Of special note, the PANSS item of “hostility” is also used to measure effect of interventions over time but is loosely defined as “verbal and nonverbal expressions of anger and resentment, including sarcasm, passive-aggressive behavior, verbal abuse, and assaultiveness” [5]. Rated on a scale of 1 (absent) to 7 (extreme), mild hostility (a rating of 3) is defined as follows: “The patient shows indirect or restrained communication of anger, such as sarcasm, disrespect, hostile expressions and occasional irritability.” More serious behaviors are not captured until the higher end of the scale.
Agitation
In addition to the early offering of medications, acute interventions that target agitation ordinarily also involve environmental and behavioral approaches, discussed elsewhere [6]. Goals include calming the agitated patient as rapidly as possible, decreasing the likelihood of harm to self or others, allowing the taking place of diagnostic tests and procedures, attenuating psychosis, and decreasing the need for seclusion or restraint (a time where staff and patient injury can occur). The induction of sleep is not desirable when evaluating a patient; sedation that necessitates constant observation and assistance in toileting places an excessive burden on staff time [7].
Diagnostic considerations center on ruling out somatic causes of the change in mental status; somatic causes may preclude the use of antipsychotic medication. An example would be acute withdrawal from alcohol or benzodiazepines where the preferred medication intervention would be a benzodiazepine such as lorazepam. This is not a trivial consideration, as it is estimated that approximately half of all patients with schizophrenia have a comorbid drug or alcohol abuse problem [8]. More unusual, but problematic, would be the presence of an underlying metabolic, toxic, or infectious process resulting in agitated behavior in a person otherwise well-known to the provider as a person with a chronic psychotic disorder.
Medication approaches usually involve drugs and formulations that have a rapid onset of action. This usually means that the therapeutic agent has a short Tmax and high Cmax; this often, but not always, requires parenteral administration. Interventions that have a high response rate for inducing calm without oversedation or other problematic adverse effects are desirable. Interventions that are easy to use, and for which clinicians have experience with, are often reached for first – even though patient acceptability may not be optimal. Commonly used in emergency departments to treat acute agitation are the intramuscular (IM) formulations of haloperidol or lorazepam, or the combination of both agents, often in the same syringe. This combination may be more efficacious and faster acting than haloperidol or lorazepam alone, and may be associated with fewer problems with extrapyramidal symptoms and akathisia than haloperidol alone [9]. However, it is unlikely that this regimen would be used as a long-term treatment option, given the availability of better-tolerated second-generation antipsychotics. Moreover, it is not desirable to chronically administer benzodiazepines because of problems of physiological tolerance, risk of withdrawal, and no or little effect on the core symptoms of psychosis [7]. Table 20.1 provides an outline of additional considerations for haloperidol and lorazepam, and for the alternative agents discussed below.
The second-generation antipsychotics ziprasidone, olanzapine, and aripiprazole are available in short-acting intramuscular formulations. They are US Food and Drug Administration (FDA)-approved for the indication of agitation associated with schizophrenia (all three) and agitation associated with bipolar mania (olanzapine and aripiprazole). Akathisia and dystonia can be avoided by using these agents rather than haloperidol, and all three agents allow for smooth transition to long-term oral therapy, as tested in IM-to-oral transition studies [10–14].
Ziprasidone IM
There are two pivotal studies, each comparing a therapeutic dose of ziprasidone vs. 2 mg [15,16]. There appears to be a dose response with 20 mg IM being superior to 10 mg IM, as measured by change in BARS scores [17], where the number needed to treat (NNT) for response vs. 2 mg at 2 hours after injection was 4 for 10 mg and 2 for 20 mg. NNT for response for the pooled doses (10 mg and 20 mg) was 3. Somnolence, nausea, and dizziness were more common with 20 mg than with 10 mg or placebo [18].
Olanzapine IM
The short-acting IM formulation was evaluated in four randomized, double-blind placebo and active comparator studies in patients with schizophrenia [19,20], bipolar mania [21], and dementia [22] (not FDA-approved for this indication). Superior onset of efficacy to haloperidol IM and lorazepam IM was observed with no adverse event significantly more frequent for IM olanzapine vs. IM haloperidol or IM lorazepam. The optimal dose is 10 mg (2.5 to 5.0 mg for vulnerable patients, e.g., elderly). NNT for response vs. placebo as measured by the PEC at 2 hours after injection is 3 [17].
Aripiprazole IM
The short-acting IM formulation was evaluated in four randomized, double-blind placebo and active comparator studies in schizophrenia [23,24], bipolar mania [25], and dementia [26] (not FDA-approved for this indication). The optimal dose is 9.75 mg (5.25 mg for vulnerable patients, e.g., elderly). The NNT for response vs. placebo as measured by the PEC at 2 hours after injection is 5, which although is not as favorable as for ziprasidone (NNT 3) or olanzapine (NNT 3), is similar to that observed with haloperidol IM or lorazepam IM from pooled data (NNT 4), with 95% confidence intervals that overlap [17].
Inhaled loxapine
This product received approval in 2013 for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults. Inhaled loxapine was evaluated in three double-blind, placebo-controlled, randomized trials in patients with schizophrenia [27,28] and bipolar mania [29]. It is the first nonparenteral agent approved for such a purpose, and potentially represents a less intrusive and stigmatizing means of delivering an anti-agitation agent. The optimal dose is 10 mg. Efficacy was noted as early as 10 minutes post-administration, which was the earliest time point measured. NNT for response for 10 mg vs. placebo at 2 hours after administration as measured by the PEC in the Phase III studies was 4 for patients with schizophrenia and 3 for patients with bipolar mania [30,31]. In the USA, the recommended dose is 10 mg with only a single dose within a 24-hour period permitted. At the present time, inhaled loxapine can be administered only by a healthcare professional in an enrolled healthcare facility. Because of the risk of bronchospasm, a Risk Evaluation and Mitigation Strategies (REMS) program is in place, and prior to administering inhaled loxapine, patients must be screened for a history of pulmonary disease and examined by chest auscultation for respiratory abnormalities such as wheezing. After administration, patients are required to be monitored for signs and symptoms of bronchospasm at least every 15 minutes for at least 1 hour.
Sublingual asenapine
Asenapine is a second-generation antipsychotic indicated for the treatment of schizophrenia, and for the acute treatment of manic or mixed episodes associated with bipolar I disorder [32]. The only available formulation of asenapine is as an orally disintegrating tablet. In contrast to the orally disintegrating tablets of olanzapine, risperidone, and aripiprazole, asenapine is administered sublingually and is absorbed in the oral mucosa, bypassing first-pass metabolism [33]. In a double-blind, placebo-controlled, randomized study of agitated adults presenting for treatment in an emergency department, sublingual asenapine 10 mg was efficacious in the treatment of agitation with an effect size comparable to that observed in prior studies of intramuscular antipsychotics [34]. NNT for response vs. placebo as measured by the PEC at 2 hours after administration was 3. At the present time, asenapine does not have regulatory approval for this indication, but the relative ease of use merits further consideration.
What do guidelines say?
For psychosis-driven agitation in a patient with a known psychiatric disorder (e.g., schizophrenia, schizoaffective disorder, bipolar disorder), current guidelines for the management of agitation recommend that antipsychotics be used instead of benzodiazepines because antipsychotics address the underlying psychosis [35]. In addition, second-generation antipsychotics with data supporting their use in acute treatment of agitation are preferred over haloperidol and other standard neuroleptics administered either alone or with an adjunctive medication.
Persistent Aggressive Behavior
Persistent aggressive behavior may be related to psychosis, psychopathy, impulsivity, co-occurring substance or alcohol use, cognitive impairments, or underlying somatic conditions. Adverse drug reactions such as akathisia can be subtle and are often missed. Thus effective treatment approaches can vary considerably depending on the specific characteristics of the individual being treated [36].
Patients with schizophrenia who are aggressive can exhibit greater severity of positive symptoms than nonaggressive patients, as observed experimentally using the PANSS [37].
Psychopathy can also be a predictor of violence and recidivism in offenders and is usually associated with “instrumental aggression” (i.e., aggression that is planned and goal-directed) [38]. Psychopathy, as defined by an arrogant/deceitful interpersonal style, deficient affective experience, and impulsive/irresponsible behavioral style [39], can be measured using a specially designed checklist, and persons with schizophrenia who are violent score significantly higher on this checklist than those who are not violent [38].
Impulsivity can further complicate a clinical picture. Substances/conditions (alcohol, attention deficit disorder, traumatic brain injury) that diminish behavioral inhibition are linked with increased aggression. Violent subjects make more impulsive errors on experimental tasks and score higher on self-ratings of impulsivity [36]. Impulsive or “affective” aggression is ordinarily unplanned, unprovoked, or out of proportion to the provocation (“hairtrigger” response), and there is often subsequent remorse.
When using an assault interview checklist to attempt to tease out psychotic, psychopathic, and impulsive factors among psychiatric inpatients who were involved in aggressive incidents, it was apparent that multiple factors are often present in a single event, and that individuals sometimes assault for different reasons at different times [40]. This heterogeneity renders treatment of aggression challenging. Although hallucinations, delusions, and psychotic misinterpretation can be treated with antipsychotics, impulsivity is more difficult to control despite best efforts with adjunctive anticonvulsants, and psychopathy has no known effective pharmacological treatment.
Within this context, oral antipsychotics that were used for acute treatment in an individual are logical choices for maintenance treatment. It is useful to have multiple formulations, including long-acting injectables [41]. If aggressivity persists, there is a limited array of evidence-based pharmacological interventions, of which clozapine has the most support.
Clozapine
A specific anti-aggressive effect was first demonstrated in a retrospective analysis of data that were collected among 223 inpatients where reductions in the Brief Psychiatric Rating Scale hostility item score were statistically independent of changes in conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content [42]. Subsequently, two randomized, double-blind, controlled trials demonstrated this effect as well. The first was a study of 157 hospitalized patients with schizophrenia or schizoaffective disorder and a history of suboptimal treatment response randomized to receive clozapine, olanzapine, risperidone, or haloperidol for 14 weeks [43]. The PANSS hostility item scores of patients taking clozapine demonstrated significantly greater improvement than those of patients taking haloperidol or risperidone, and this effect was independent of the antipsychotic effect of clozapine on other rating scale items that reflect delusional thinking, a formal thought disorder, or hallucinations and independent of sedation. In the same study, clozapine also evidenced superiority regarding reduction of number and severity of incidents of overt aggression [44]. Confirming these findings were the results of a double-blind, 12-week study of 110 hospitalized patients with schizophrenia selected because they exhibited violent behaviors and where subjects randomized to clozapine had greater reductions compared to olanzapine and haloperidol in the number and severity of physical assaults [45]. Olanzapine was also superior to haloperidol in reducing the number and severity of aggressive incidents on these measures. These effects were independent of antipsychotic effects as measured by the PANSS.
Clozapine, although potentially a life-saving treatment, can also be life-threatening [46]. Because of clozapine’s risk for agranulocytosis, patients receiving clozapine require enrollment in a registry, and frequent white blood cell count monitoring is required. Other safety concerns include myocarditis, seizures, and weight gain/metabolic abnormalities. Nonetheless, despite clozapine’s perceived dangerousness, data on control of aggressive behavior make this antipsychotic a compelling choice for many patients with schizophrenia. Moreover, although clozapine was initially approved for treatment-resistant schizophrenia, clozapine subsequently received approval for reduction in the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorders.
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Inpatient aggression in community hospitals
The appropriateness of treating psychopathic disorders
Is impulsive violence an addiction? The Habit Hypothesis
Effectiveness of antipsychotic drugs against hostility in patients with schizophrenia in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study
Crime, violence, and behavioral health: collaborative community strategies for risk mitigation
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