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Clozapine: Knowing its flaws to optimize its potential

Clozapine: Knowing its flaws to optimize its potential

When people find out what my job is, it is frequent that I hear jokes about me psychoanalyzing them or suggesting that their friends or relatives need a visit from me! I am an Italian psychiatrist and PhD student in Life Sciences at University Magna Graecia of Catanzaro (Italy), working in everyday clinical psychiatric practice, and am passionate about research and studying neurosciences, psychopharmacology, and mental health.

Even if I have already heard similar jokes hundreds of times, this has not (yet) affected my desire to study the human mind and behavior, and to try to alleviate the suffering that psychiatric disorders bring to people.

Cover art for the album Quadrophenia by the artist The Who

In this blog, I will briefly discuss schizophrenia and clozapine, the drug that is prescribed to patients who do not respond to other agents. I will also discuss my own research interests on this topic.

What is Schizophrenia?

Schizophrenia is one of the most severe disorders in psychiatry, and its diagnosis has a lot of impact and meaning for both clinicians and patients.

Melancholy, 1894 by Edvard Munch

Its name, deriving from ancient Greek, has a historical and descriptive value, and literally means “split mind”. However, its use over time has taken on a negative meaning and has often been the main synonymous with “madness” or mental illness in general, thus gaining an intrinsic stigma. In this regard, this has even led to the proposal to rename schizophrenia as something simpler and more descriptive such as “salience disorder”, “mind-split-disease” or “integration disorder”, or still as a more neutral version such as “Bleuler’s syndrome”.

One: Number 31, 1950 by Jackson Pollock

Managing schizophrenia involves a complex interplay between early diagnosis, family support, psycho-education, psychotherapy, and prompt rehabilitation, where a fundamental role is played by pharmacological treatment.

The name of the entire category of drugs used to treat schizophrenia derives from the action against the most prominent symptoms, namely “antipsychotics”.

Clozapine’s critical role

The first antipsychotic drug, chlorpromazine, was synthesized in the ’50s, and initially used as an anaesthetic. Then, the French military surgeon Henri Laborit understood its antipsychotic properties in an attempt to prevent shock and noted that it produced a “euphoric quietude” in soldiers, thus transforming it into the first neuroleptic drug of history and the forefather of the following first-generation antipsychotics.

Over the decades, many other antipsychotic molecules were developed, until clozapine made its appearance on the scene in the 1970s.

Clozapine, the progenitor of the second generation of antipsychotics, has brought a breakthrough in the antipsychotic properties of the treatment of schizophrenia, being the first to control the symptoms of the disorder with a tangible clinical improvement, and a resumption of the patients’ overall functioning, even in patients who had not improved with other antipsychotic medications. Clozapine has thus conquered a unique role in the treatment of schizophrenia, also becoming the only drug with effect in “treatment-resistant schizophrenia”, which is when the other antipsychotics are not effective on the disease.

Guernica, 1937 by Pablo Picasso

However, despite its positive clinical impact, clozapine had a complicated fate, and it was even temporarily withdrawn from the market in the 1970s, due to a series of unforeseen deaths and after reports of agranulocytosis, a severe condition in which the bone marrow does not make enough of a certain type of white cell, most often neutrophils (a kind of white blood cells that protect from infections). That was the darkest period in its history, and we risked never using such an important drug in psychopharmacology.

It was only thanks to important subsequent studies published in the late ’80s that it was understood that clozapine, while burdened with important and unpredictable side effects, shows an unmatched efficacy in treatment-resistant schizophrenia. Thus, it was finally approved by FDA in 1990. We also learnt that these unpredictable side effects could be identified early through regular blood tests.

Cover art from the album Hotel California, 1976 by Eagles

Since then, despite the important corollary of associated adverse events, the risk-benefit ratio of clozapine has been considered acceptable when using a specific protocol that includes a strict administration schedule and an extensive safety check, and especially full blood test (checking for white blood cells, associated with immune system functioning) that is mandatory in all countries but slightly different around the world. For example in the UK it is weekly for the first 18 weeks, then biweekly from 19 to 52 weeks, then monthly as long as taking clozapine, with temporary stop or discontinuation in case of neutropenia, that is a blood condition with low levels of neutrophils.

Clozapine-related DRESS syndrome

My research interest with clozapine is due to a rare but very interesting condition called “Drug reaction with eosinophilia and systemic symptoms” (DRESS).

DRESS syndrome is a rare but potentially fatal condition associated with various drugs including antibiotics, allopurinol, other psychopharmacological agents such as carbamazepine, and, as identified more recently, clozapine. To date, this condition is not predictable and there are no definitive treatment guidelines, therefore its early recognition remains the main tool available.

For a long time we did not know that clozapine could be implicated in this syndrome, since many of the symptoms used for diagnosis (e.g., eosinophilia, internal organ involvement, fever) are actually common adverse events that have already been associated with clozapine. Therefore, clozapine-related DRESS syndrome may have been oversighted and underestimated. Indeed, my research is mainly focused on better understanding clozapine's role in DRESS syndrome, and, to date, we already found 27 new cases of clozapine-related DRESS syndrome and the count is still ongoing through the screening of large international pharmacovigilance databases.

Untitled (people), 1985 by Keith Haring — All Keith Haring Artwork © Keith Haring Foundation Courtesy of Nakamura Keith Haring Collection.

However, the identification of this or other side effects should not discourage the use of such an important drug for schizophrenia treatment. Rather, knowing its characteristics, mechanisms and potential interventions should increase awareness and improve general management of clozapine to optimize its safe use despite its important side effects profile.


Artwork exhibition by Mike Kelley at MoMA PS1, New York, 2013-2014 —

In conclusion, clozapine has had many ups and downs along its path, and it undoubtedly still remains fascinating and enigmatic in many ways. Its history, its effectiveness and the mystery of its unique action make it one of the most interesting medications in psychiatry.

Until we have something safer and more effective to replace it, we need to understand how to best use it in the people who can benefit most from it.


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