Fifty years of experience with loxapine for the rapid non-coercive tranquilization of acute behavioral disturbances in schizophrenia patients, and beyond

ABSTRACT

Introduction

Acute behavioral disturbances in psychosis, including agitation, comprise a heterogeneous group of manifestations varying in intensity and duration they last for. They require rapid, non-coercive treatments ranging from verbal de-escalation to the calming effect of pharmacological agents. The treatment goals are reduction of patient suffering and prevention of disease deterioration. Stabilizing rather than sedating is preferred to ensure improved compliance and a stronger therapeutic alliance. Furthermore, animal pharmacology and clinical studies on agitation reveal the robust calming and anxiolytic properties of loxapine.

Areas covered

This review covers the pharmacological and clinical history of loxapine along with research developments. It emphasizes the advantages of its multiple formulations ranging from injectable forms and tablets to orally inhaled forms to attain rapid and fine-tuned tranquilization.

Expert Opinion

Rapid tranquillization is achieved within 2–6 hours using liquid orally-consumed loxapine, and within an hour or less with its IM or orally inhaled forms. Loxapine has been adopted in the management of a wide range of acute disturbances, such as agitation in psychosis. In the context of personalized medicine, key cellular and molecular elements of the schizophrenia phenotype were recently shown to be improved with loxapine.

KEYWORDS:

• Agitation
• acute psychosis
• behavioral disturbances
• bipolar disorder
• hostility
• loxapine
• stabilization
• schizophrenia

Article highlights

• Loxapine was introduced in the 1970s as an antipsychotic (AP) drug to treat schizophrenia. This compound is the only representative of the dibenzoxazepine family of APs. Preclinical studies, early clinical trials, and practice have shown strong sedative, as well as anxiolytic effects.

• Pure sedation is not the appropriate response to treat the various acute behavioral disturbances of psychosis and should be replaced with rapid tranquilization, allowing active patient participation. In addition to staff training and de-escalating procedures, loxapine is an interesting medication option to achieve this treatment goal. Therefore, new loxapine formulations (oral solution, intramuscular injection, and oral inhaler) were developed to achieve this therapeutic goal.

• Among the acute manifestations of psychosis, agitation was shown to be controlled within 2–6 hours with loxapine’s oral liquid concentrate. Clinical studies have demonstrated that rapid tranquilization can be achieved in an hour or less with intramuscular (IM) or orally inhaled loxapine.

• Non-coercive rapid tranquilization in emergency services and acute hospitalization settings is often the first step toward the establishment of an optimal stabilization treatment. These therapeutic benefits constitute the main innovation generated by fifty years of experience with loxapine.

• Recent studies on reprogrammed fibroblasts from patients with schizophrenia have shown that key cellular and molecular elements of the schizophrenia phenotype can be modulated with loxapine. These results open new avenues of research for future therapeutic targets.

Declaration of interest

P Nuss has received honoraria or consulting fees from Eisai, Gilead, Lundbeck, Novartis, Otsuka, and Sanofi. E Corruble lectures for Eisai on schizophrenia. E Baloche is an employee of Eisai. RP Garay is President of Craven (Villemoisson-sur-Orge, France), and Craven received honoraria for writing a draft of this article. PM Llorca has received grants, honoraria, or consulting fees from Eisai, Gedeon Richter, Janssen, Lundbeck, Otsuka, Sanofi and Teva. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A peer reviewer on this manuscript has received manuscript or speaker’s fees from Astellas, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Elsevier Japan, Janssen Pharmaceuticals, Kyowa Yakuhin, Lundbeck Japan, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Nihon Medi-Physics, Novartis, Otsuka Pharmaceutical, Shionogi, Shire, Takeda Pharmaceutical, Tsumura, Wiley Japan, and Yoshitomi Yakuhin, and research grants from Dainippon Sumitomo Pharma, Eisai, Mochida Pharmaceutical, Meiji Seika Pharma and Shionogi. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Scientific accuracy review

EISAI provided a scientific accuracy review at the request of the journal editor.

Additional information

Funding

Eisai SAS (La Defense, France) provided financial support.