Intramuscular ziprasidone(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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.
Randomized controlled trials of antipsychotics are summarized in the Table. Two randomized, controlled, double-blind trials were designed a priori to study aggression in schizophrenia. The first trial compared clozapine(Drug information on clozapine), olanzapine, risperidone(Drug information on risperidone), and haloperidol(Drug information on haloperidol) in 157 patients with schizophrenia or schizoaffective disorder.28 The hostility item of the PANSS (Positive and Negative Syndrome Scale) was used as a proxy measure for aggression in the analyses. Clozapine was superior to risperidone and haloperidol (but not to olanzapine) in reducing hostility.29 Neither risperidone nor olanzapine showed superiority to haloperidol.
In the same randomized controlled trial, incidents of overt physical aggression were also recorded and analyzed.28,30 The results showed clozapine (and, in some analyses, all 3 atypicals) to be superior to haloperidol in antiaggressive efficacy, particularly after the first 24 days in the trial, when scheduled dose escalation of clozapine was completed. Thus, an important clinical take-home lesson from this study is that full effectiveness of clozapine cannot be expected until the patient has been exposed to an adequate-dose regimen. If aggressive behavior is a problem during the escalation period of clozapine, other medications need to be temporarily coadministered. Discontinuation of clozapine for lack of effectiveness during this period would be premature.