Clozapine’s critical role in treatment resistant schizophrenia: ensuring both safety and use

ABSTRACT

Introduction: Clozapine was first introduced as an antipsychotic in the 1970‘s but a cluster of deaths, later linked to the drug’s risk of agranulocytosis, led to its withdrawal in most countries. However, work in the 1980’s established its unique efficacy in treatment resistant schizophrenia (TRS), which constitutes as many as 30% of those with the illness. Clozapine was reintroduced with this indication shortly thereafter, but because of this risk its use requires routine hematologic monitoring.

Areas covered: An update is provided regarding clozapine’s risk of neutropenia, agranulocytosis, and associated mortality. In addition, updates are provided on other side effects, specifically myocarditis and bowel obstruction, as evidence suggests these are more common than agranulocytosis and associated with higher mortality rates.

Expert opinion: Clozapine remains the only treatment indicated in TRS, but it is dramatically underutilized. Clearly there are serious side effects associated with its use, and while the focus has historically been on hematologic concerns, we highlight other side effects that also demand systematic monitoring. Because it is the only effective treatment option we have for TRS, though, efforts must be implemented that ensure its use in this population while maximizing safety.

KEYWORDS:

• Clozapine
• treatment resistant schizophrenia
• side effects
• neutropenia
• agranulocytosis
• myocarditis
• bowel obstruction

Article highlights

• Clozapine is the only antipsychotic with an indication for treatment-resistant schizophrenia (TRS).

• Deaths related to its risk of agranulocytosis have decreased with routine hematological monitoring.

• Myocarditis and bowel obstruction also require systematic monitoring as they occur more frequently than agranulocytosis and are associated with increased mortality rates.

• Despite these risks, clozapine is associated with decreased mortality rates.

• Clozapine continues to remain markedly underutilized in TRS even though it is the only treatment with clearly established efficacy.

This box summarizes key points contained in the article.

Declaration of interest

G Remington has received research support from Novartis and consultant or speaker fees from Neurocrine Biosciences, Novartis, and Synchroneuron. J Lee has received consultant or speaker fees from Roche. O Agid has received research support from Janssen Ortho (Johnson & Johnson) as well as Sunovion, and consultant or speaker fees from Janssen Ortho (Johnson & Johnson), Lundbeck, Mylan Pharmaceuticals, Novartis, Otsuka, and Sunovion. H Takeuchi has received consultant or speaker fees form Dainippon Sumitomo Pharma. G Foussias has received consultant or speaker fees from Roche. V Powell has received consultant or speaker fees from Novartis. 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 apart from those disclosed.