Physician’s Weekly: online CME courses, articles on hypertension, arthritis

Patients with schizophrenia and other psychotic disorders sometimes experience acute agitation and are often admitted to emergency rooms or psychiatric hospitals. Since such agitation is usually accompanied by violent and/or destructive behavior, rapid intervention is often required to protect both the patient and caregivers. One common intervention strategy involves an injectable "cocktail" of haloperidol and lorazepam with an additional injection of benztropine mesylate for potential extrapyramidal side effects. These injections are often given every 2 hours until the patient is sedated or the agitation is controlled.

Most cases of acute agitation are short lived, but there are several long-term consequences to consider. The older antipsychotics such as intramuscular (IM) haloperidol or fluphenazine are associated with troublesome side effects involving the extrapyramidal system. Even though the agitation may have been successfully treated, patients may still remember the side effects and be hesitant to use drugs in the future.

New IM Formulations Offer Hope

Pharmaceutical developers have recently created newer IM formulations of several of the second-generation antipsychotic medications for the management of acute agitation in schizophrenia. In 2006, the FDA approved an injectable form of immediate-acting aripiprazole for IM use in adults with schizophrenia or bipolar mania who are experiencing agitation.

The efficacy of IM aripiprazole in controlling agitation was evaluated in three short-term (24-hour), randomized, double-blind, placebo-controlled studies in patients with schizophrenia (two of the studies) and bipolar I disorder (the other study) involving a total of 1,086 patients. Each of these trials included a single active comparator treatment arm of either haloperidol injection (schizophrenia studies) or lorazepam injection (the bipolar study). The two studies in schizophrenia showed that treatment with IM aripiprazole resulted in a significant reduction in agitation within 45 to 60 minutes, was generally well tolerated, and wasn’t associated with excessive sedation. Comparable findings were reported in patients with bipolar I disorder.

It should be noted that patients enrolled in these trials needed to be clinically agitated, exhibiting a level of agitation that could range from moderate to severe as measured by the Positive and Negative Syndrome Scale (PANSS) Excited Component (eg, poor impulse control, tension, hostility, uncooperativeness, and excitement items). Patients were also clinically appropriate for treatment with an IM medication.

In the three investigations, the primary efficacy measure used for assessing agitation signs and symptoms in these trials was the change from baseline in the PANSS Excited Component (PEC) at 2 hours post-injection. IM aripiprazole was statistically superior to placebo on mean change in the PEC score versus placebo; this IM agent was not statistically different from IM haloperidol on PEC scores. Also of importance, extrapyramidal symptom-related adverse event rates were similar for IM aripiprazole (1.7%) and placebo (2.3%), and were higher with haloperidol (12.6%). Thus, this new formulation of aripiprazole enables clinicians to treat agitation as effectively as with the older medications without extrapyramidal side effects. It’s well tolerated and appears to reduce levels of acute agitation without sedation. The lack of a significant side-effect profile with IM aripiprazole can favorably impact future acceptance of and adherence to future antipsychotic therapy.

An Additional Advantage

Another important note is that IM aripiprazole may potentially be used to treat patients for several days. As the agitation is controlled, there may be an accompanying improvement in the psychotic symptoms. In these cases, patients may be seamlessly switched from a daily injection to an oral dose of aripiprazole because the IM and oral doses are equivalent.

Richard C. Josiassen, PhD has indicated to Physician’s Weekly that he has worked as a consultant for Otsuka Maryland Research Institute. He has also worked as a paid speaker for Bristol Myers Squibb. In addition, Dr. Josiassen has received grants/research aid from AstraZeneca, Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceuticals, Otsuka Maryland Research Institute, Pfizer, and Yamanuchi.