Schizophrenia affects 23 million people worldwide.1 Agitation is a common — and costly — issue associated with the psychiatric condition. As such, early identification and quick intervention are the keys to ensuring that agitation doesn’t escalate into more aggressive behavior.

Accepted guidelines emphasize the need for noncoercive management strategies to protect the trusted therapeutic alliance between patients and their healthcare providers.1 Further, rapid response to agitation is necessary for avoiding the traumatic and costly use of coercive techniques like physical restraint and seclusion, which require admission and prolonged hospitalizations.1

Common medications used for the acute treatment of agitation in psychiatric patients include first-generation antipsychotics (FGAs), second-generation antipsychotics (SGAs), and benzodiazepines (BDZs).2 There are 3 methods of administration: oral, intramuscular, and intravenous. At times, agitated patients may initially accept oral medications, but may spit them out or need a relatively long time to achieve symptom relief after oral administration.2 Because several SGAs (olanzapine, ziprasidone, and aripiprazole) are available in immediate-release formulations, these are often the first-choice antipsychotics, together with BDZ, for the acute treatment of agitated patients with schizophrenia.2

However, there is a need for a fast-acting treatment for agitation that doesn’t require injection. While injection-delivered medications can be effective, that method of delivery can ratchet up a patient’s level of agitation.

The Promise of Loxapine

Loxapine, an established, FGA agent, is approved for the treatment of acute agitation in patients with schizophrenia. The clinical effects of loxapine are likely due to its antagonism of dopamine D2 receptors.3 Loxapine rebalances dopamine and affects serotonin to improve thinking, mood, and behavior4:

The intramuscular loxapine formulation that was previously approved is no longer available in the United States.5 However, the medication has been reformulated at a lower dose, producing an inhaled powder that can be directly administered to the lungs. Clinical studies have confirmed the efficacy, rapid onset, safety, and tolerability of this formulation in both psychiatric emergency and hospital settings.1 Recent research indicates that inhaled loxapine potentially can be self-administered in the community setting without the direct supervision of a healthcare professional.1

Inhaled loxapine is administered through a hand-held, single-dosage, disposable breath-actuated tool designed to quickly deliver drug dry powder into the alveoli, with intravenous like pharmacokinetics leading to a rapid systemic effect.2 The entire process of drug delivery commonly happens in less than 1 second.2 However, it’s important to note that some degree of patient cooperation is necessary for administration, so this formulation may not be recommended to highly agitated patients.2

The Symptoms of Schizophrenia-Related Agitation

Psychotic symptoms have long been associated with agitation or violence, resulting in an increasingly perceived stigma of psychiatric disorders.2 Agitation is a serious medical challenge in many patients with schizophrenia, and it can be expressed in several ways, including1,2,4:

• distortions of perception, emotion, and thinking;

• increased responsiveness to stimuli;

• hallucinations;

• delusions;

• disorganized thinking;

• hypervigilance;

• little desire to be around other people;

• trouble speaking clearly;

• lack of motivation;

• irritability;

• hyperactivity;

• hostility;

• tension;

• verbal outbursts;

• wandering;

• pacing;

• rapid speech;

• restlessness; and

• increased risk for suicide.

Comorbid conditions, including substance and alcohol abuse, certain personality disorders, and lack of medication compliance, can contribute to agitation.2 Agitation associated with psychosis is a frequent reason for emergency department visits, admission to psychiatric inpatient units, or prolonged hospitalizations.3 Because agitation can escalate very quickly, it needs to be recognized and treated early for the most optimal outcome.3 In busy emergency departments, the speed of treatment onset is generally the most important criterion when selecting anti-agitation medication.4 Ideally, however, the escalation of agitation should be prevented to reduce emergency department visits and save money and resources.3

How Loxapine Affects Agitation Symptoms

Inhaled loxapine has received regulatory approval from the US Food and Drug Administration and the European Medicines Agency for use in adults.3 Both bodies stipulate that inhaled loxapine can only be used in healthcare facilities under restricted conditions.3

The Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) is a clinical scale used to assess the level of agitation in patients. It assesses 5 symptoms: poor impulse control, tension, hostility, uncooperativeness, and excitement. Phase II/III clinical trials in patients with schizophrenia found that inhaled loxapine given in the hospital setting significantly reduced agitation in 2 hours compared with placebo, as measured by PANSS-EC.3 In fact, a significant decrease in agitation over placebo was seen after only 10 minutes.3

Inhaled loxapine may have some advantages when compared with other drugs available to treat acute agitation, including2:

•  a significant utility benefit when compared with injections or tablets;

• rapid onset of the anti-agitation effect (within a couple of minutes, on average);

• a less invasive, needle-free method of delivery;

• bypassing the gastrointestinal system, increasing bioavailability; and

• no effect on cardiac repolarization.

The effectiveness of inhaled loxapine has been evaluated in 2 published case series on patients with borderline personality disorder and dual diagnosis patients. In those studies, inhaled loxapine was proven to be effective and well-tolerated when used by agitated patients with schizophrenia.2 Additionally, inhaled loxapine’s effect on agitation in patients with schizophrenia was investigated in 2 Phase III clinical trials. Patients were randomly assigned to receive either inhaled loxapine 5 mg, inhaled loxapine 10 mg, or a placebo. A reduction in agitation of ≥40% in PANSS-EC score was observed in about 20% of patients with schizophrenia 10 minutes after receiving inhaled loxapine.5 This reduction was seen in patients receiving both the 5 mg and 10 mg doses.5 Further, significant changes in Clinical Global Impression-Improvement (CGI-I) scores were noted, with more patients in the loxapine-treated groups classified as much improved and very much improved compared with the placebo group.5

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In another study, researchers evaluated 129 agitated patients with schizophrenia or schizoaffective disorder who were randomly assigned to receive either a single inhalation of 5 mg or 10 mg of loxapine or a placebo in a clinical or hospital setting. During the phase II randomized, double-blind, placebo-controlled study, inhaled loxapine produced a rapid improvement in agitated patients.2 Statistically significant differences in efficacy were found for the 10 mg dose when compared with the placebo.2

In another phase III, randomized, double-blind, placebo-controlled, parallel-group study of 344 agitated patients with schizophrenia, inhaled loxapine was an effective treatment for agitation, and both the 5 mg and 10 mg doses resulted in significantly larger decreases in PANSS–EC scores during the 2 hours after the first dose.2

The Risks of Loxapine

Using loxapine does come with some risks, including2,4:

• respiratory distress, including asthma or wheezing;

• altered sense of taste;

• throat irritation;

• mild sedation;

• tardive dyskinesia, a condition marked by grimacing, sucking, and smacking of lips, or other movements that you cannot control;

• sudden cardiac death due to arrhythmia; and

• neuroleptic malignant syndrome, a rare, life-threatening condition that causes confusion, fever, extreme muscle stiffness, and sweating.

Prior to administering inhaled loxapine, patients should be screened for a current diagnosis or history of asthma, chronic obstructive pulmonary disease, or other lung diseases; acute respiratory symptoms or signs; current use of medications used to treat airway disease; and any respiratory abnormalities.2 Other medications taken into the lungs may interfere with the effectiveness of the aerosol formulation of loxapine.2

Some additional disadvantages of using inhaled loxapine should be considered. Because some level of patient collaboration is required to administer the medication, it should not be the first-line treatment for severe agitation in uncooperative patients.2 Additionally, healthcare facilities using inhaled loxapine are required to have immediate, onsite access to equipment and personnel trained to manage acute bronchospasms, including advanced airway management.2

Another concern may be the costs of inhaled loxapine. In the United States, the costs are relatively higher than those of the oral and intramuscular medication currently used to treat agitation in psychiatric disorders.2

Treating Agitation at Home

Antiagitation treatments that are fast-acting, well-tolerated, and easy to administer without being supervised by a healthcare professional remain elusive. Research suggests that the decision-making ability of patients with schizophrenia is not impaired.5 However, unsupervised self-treatment comes with risks, such as patients treating themselves unnecessarily or taking too many or higher doses than prescribed.5

An open-label study currently underway in 5 European countries is investigating the safety of self-administering inhaled loxapine outside the hospital setting.3 The primary focus is on serious adverse events, including respiratory events, related to inhaled loxapine.

During the study, each eligible patient will have a baseline hospital visit and will be given a single-dose inhaler containing 10 mg of loxapine and a short-acting beta-agonist bronchodilator as rescue medication for possible severe respiratory side effects. Participants also will be given instructions on how to store and use inhaled loxapine and how to identify the onset of agitation. Any new episodes of agitation will be recorded on the patient’s diary card, with caregiver support. In addition, patients who show improvement of agitation within 2 hours after self-administration of inhaled loxapine will be asked to evaluate their satisfaction with treatment on a 5-point Likert scale at a follow-up hospital visit with the study investigator. The study is expected to be completed in December 2019.6

Summary

Using an innovative delivery system, inhaled loxapine has proven to be effective and generally well-tolerated when administered to agitated patients with schizophrenia and bipolar disorder, with relatively fast results.2 Recent research indicates that inhaled loxapine potentially can be self-administered in the community setting without the direct supervision of a healthcare professional.1

References

1. Pacciardi B, Calcedo A, Messer T. Inhaled loxapine for the management of acute agitation in bipolar disorder and schizophrenia: expert review and commentary in an era of change. Drugs R D. 2019;19(1):15-25.

2. de Berardis D, Fornaro M, Orsolini L, et al. The role of inhaled loxapine in the treatment of acute agitation in patients with psychiatric disorders: a clinical review. Int J Mol Sci. 2017;18(2):349.

3. Gil E, Garcia-Alonso F, Boldeanu A, Baleeiro Teixeira T. Safety and efficacy of self-administered inhaled loxapine (ADASUVE) in agitated patients outside the hospital setting: protocol for a phase IV, single-arm, open-label trial. BMJ Open. 2018;8(10):e020242.

4. National Alliance on Mental Illness. Loxapine (Loxitane). NAMI. https://www.nami.org/Learn-More/Treatment/Mental-Health-Medications/Loxapine-(Loxitane). Accessed March 27, 2019.

5. Zeller S, Zun L, Cassella JV, Spyker DA, Yeung PP. Response to inhaled loxapine in patients with schizophrenia or bipolar I disorder: PANSS-EC responder analyses. BJPsych Open. 2017;3(6):285-290.

6.. U.S. National Library of Medicine. Phase IV to Evaluate the Safety of Self-administered ADASUVE® in Agitated Patients Outside the Hospital Setting. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02525991. Accessed March 27, 2019.