Psychopharmacology of Aggression and Violence in Mental Illness

Most patients with mental illness are not violent, and when violent behavior does occur, it is usually transient.¹ Nevertheless, violent behavior is a challenging problem. Swanson and colleagues ² provided evidence that demonstrated that schizophrenia and major mood disorders confer an elevated risk of violent behavior, and that risk is augmented by comorbid substance use disorders and by comorbid personality disorders.

Comorbid substance use disorders play a particularly important role in the development of violent behavior in schizophrenia. This was studied in a meta-analysis of violent criminality using data from 18,423 individuals with schizophrenia and other psychoses.³ The odds ratio for violent crime was 2.1 (95% confidence interval [CI], 1.7 - 2.7) without comorbidity, but it increased to 8.9 (95% CI, 5.4 - 14.7) with comorbidity. The difference between odds ratios indicated a marked effect of substance abuse on violent crime.

The clinical importance of this effect is underlined by the fact that risk for substance use disorders in schizophrenia is very high; lifetime prevalence of this comorbidity in schizophrenia is estimated at 47%.⁴ For these reasons, evaluation of comorbid substance use disorders is an important component of the clinical assessment of patients with schizophrenia. Management of comorbid substance use disorders must be an inherent part of the treatment plan.

Violent behavior is heterogeneous in origin, and its development is not limited to the context of mental illness.⁵ Therefore, management approaches that rely exclusively on psychopharmacology are frequently unsuccessful-not only because of incorrect societal context, but also because violent behavior in mental illness frequently results from nonadherence to treatment.⁶

Acute management of agitation and violent behavior

Agitation is a common reason for presentation to an emergency department (ED); it can tip the decision for in-patient care and can be an obsta-cle to hospital discharge. Agitation can easily escalate to aggression and violent behavior, and thus acute agitation is considered a behavioral emergency that requires immediate action. In addition to nonpharmacological interventions related to managing crisis situations, medication approaches are vital.⁵

Although oral medications can be effective, rapidity of onset of action is enhanced with the use of short-acting parenteral formulations that allow for maximal plasma levels to be reached more quickly. Lorazepam can be useful when the cause of the disturbed behavior is unclear and perhaps due to withdrawal from alcohol. It is reliably absorbed intramuscularly, has no active metabolites, and has a half-life of 10 to 20 hours; the usual dosage is 0.5 to 2 mg every 1 to 6 hours.⁷

Caution is required with lorazepam when respiratory depression is a possibility. In addition, lorazepam should not be used for long-term daily use because of the problems that are associated with benzodiazepine use-tolerance, dependence, and withdrawal.

 

What is already known about treating aggression?

? Schizophrenia and major mood disorders confer an elevated risk of violent behavior, which is further raised by comorbid substance use disorders and by comorbid personality disorders. Intramuscular short-acting formulations of lorazepam, haloperidol, aripiprazole, olanzapine, and ziprasidone are available for the management of acute agitation and aggression. All available antipsychotics as well as mood stabilizers and other drugs have been used for the long-term management of violent behavior in mental illness. Clozapine has demonstrated superiority over other treatments.

 

What new information does this article provide?

? We update information on efficacy and safety of medications used for acute agitation and aggression, particularly intramuscular formulations.

 

What are the implications for psychiatric practice?

? Clozapine is the first-choice treatment for persistently violent patients with schizophrenia. It is not likely to be fully effective before an adequate dose (approximately 400 mg/d) is reached-often several weeks. Clozapine should not be prematurely discontinued during this escalation period. If necessary, another medication may be temporarily added to control violent behavior. If clozapine cannot be used, olanzapine may be a second choice. Other antipsychotics do not show any systematic differences in their antiaggressive effects.

 

The combination of intramuscular haloperidol with intramuscular lorazepam is also commonly used and is supported by a double-blind randomized clinical trial that compared intramuscular haloperidol 5 mg, intramuscular lorazepam 2 mg, or a combination of both in psychotic, agitated, and aggressive patients treated in EDs.⁸ However, continued use of haloperidol as a foundational antipsychotic would be suboptimal in schizophrenia or bipolar disorder. Consequently, there has been increased interest in intramuscular formulations of second-generation antipsychotics, of which 3 are available in the US: ziprasidone, olanzapine, and aripiprazole.⁹

Intramuscular ziprasidone’s efficacy in reducing agitation was evidenced in 2 pivotal clinical trials that enrolled patients with schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features, or another psychotic disorder.^10,11 Although the product label recommends a dose of 10 or 20 mg, the best dose appears to be 20 mg; this conclusion is based on the proportion of patients with a clinically relevant reduction in agitation-rating–scale scores.

A naturalistic study of intramuscular ziprasidone in patients who can have more severe levels of agitation than those participating in a randomized controlled study also supports the use of intramuscular ziprasidone as an effective treatment.¹² Product labeling cautions prescribers regarding ziprasidone’s potential to prolong the QT interval and that the cyclodextrin excipient used in the formulation is cleared by renal filtration, which may be an issue in patients who have impaired renal function.¹³

Intramuscular olanzapine was found to be effective in reducing agitation in patients with schizophrenia and in patients with bipolar disorder, manic or mixed.^14-16 The recommended dose of olanzapine is 10 mg, but lower doses of 2.5 to 5 mg can be considered for medically vulnerable patients.¹⁷ Naturalistic studies of intramuscular olanzapine are also supportive of its effectiveness.¹⁸ The product label is cautionary regarding hypotension, bradycardia with or without hypotension, tachycardia, and syncope as reported during the clinical trials. Simultaneous injection of olanzapine and benzodiazepines is not recommended, and this advice is reinforced in a report of a case series in which comorbid medical conditions were noted to increase risk.¹⁹

Study findings indicate that intramuscular aripiprazole reduces agitation in patients with schizophrenia and in patients with bipolar disorder, manic or mixed.^20-22 The recommended dose is 9.75 mg.²³ The product label cautions clinicians regarding greater sedation and orthostatic hypotension with the combination of lorazepam and aripiprazole compared with aripiprazole alone.

Once past the acute phase, patients who are receiving intramuscular ziprasidone, olanzapine, or aripiprazole can be successfully transitioned to the oral counterpart of the medication.^24-27

Long-term management of violent behavior

Most of the evidence on long-term treatment of aggression in mental illness has been collected in patients with schizophrenia. There are very few controlled trials that were a priori designed to test antiaggressive treatments. Most of the data available were obtained in the form of clinical observations, uncontrolled chart reviews, and post hoc retrospective analyses of databases collected primarily for purposes other than the study of aggression. Antipsychotics are the mainstay of the long-term pharmacological treatment of aggression in schizophrenia.

Antipsychotics

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