Addressing the need for rapid treatment of agitation in schizophrenia and bipolar disorder: focus on inhaled loxapine as an alternative to injectable agents.

Agitation (excessive motor or verbal activity) can be associated with schizophrenia or bipolar mania, and can further escalate into aggressive behavior and potentially lead to injuries in patients and staff. Medications used to treat agitation include antipsychotics and benzodiazepines, usually administered intramuscularly when rapid action is desired. Loxapine, a first-generation antipsychotic, has recently been reformulated into an inhaled powder that allows for direct administration to the lungs, resulting in rapid absorption into the systemic circulation. Administered via a single-use device, inhaled loxapine was tested in randomized controlled trials in agitation associated with schizophrenia or bipolar mania; doses of 5 mg and 10 mg were found to be efficacious, with an apparent dose response. In the Phase III studies, number needed to treat versus placebo for a ≥40% reduction from baseline on the Positive and Negative Syndrome Scale - Excited Component (PANSS-EC) at 2 hours was three for patients with bipolar disorder, and five for 5 mg and four for 10 mg for patients with schizophrenia, with effect sizes comparable to what has been observed in analogous studies of intramuscular injection of antipsychotics or lorazepam. Separation from placebo on the PANSS-EC was as early as 10 minutes postinhalation, the first time point where this was measured. Dysgeusia was the most commonly encountered spontaneously reported adverse event. Adverse events related to extrapyramidal symptoms and akathisia were relatively rare. Spirometry studies identified the potential for bronchospasm particularly in persons with asthma. Because of concerns over pulmonary safety, inhaled loxapine is restricted to use in hospitals and patients need to be prescreened for the presence of pulmonary disease, as well as monitored for signs and symptoms of bronchospasm for 1 hour postdose administration, as per a Food and Drug Administration-mandated Risk Evaluation and Mitigation Strategy.