02. Does Clozapine’s Agranulocytosis Risk Persist Beyond Initial Treatment Period?

Text version

The Power of Epidemiology and Long-Term Follow-up in Medicine

In this Quick Take, I’m going to talk about a study that shows you the power of epidemiology and long-term follow-up in Medicine.

The study in question reexamines the long-term agranulocytosis risk from clozapine and I think it is very close to being a definitive study. Therefore, any clinician who treats patients with serious mental illness should know this paper from Rubio and colleagues which was published at the end of April 2024 in Lancet Psychiatry.

Background on the Finnish-Swedish Research Group

This population-based epidemiological study comes from a well-known Finnish-Swedish group of researchers, particularly Drs. Taipale and Tiihonen, who have taken advantage of the national registries from the country of Finland to examine morbidity and mortality in the Finnish population, particularly with regard to serious mental illness.

They are in a unique position to do high-quality epidemiological research because the various registries in Finland, like the medical registry, pharmacy data, or the death registry, are well-maintained and go back over a long period of time. Finland is also the country with the highest rate of clozapine use, so they are uniquely positioned to study rare events in the real world.

The FIN20 Study and Its Findings

One of the main contributions to Psychiatry from this research group was their finding in the so-called FIN20 study that the highest long-term all-cause mortality risk for patients with schizophrenia in Finland is in the group of patients who were untreated compared to patients who were treated with antipsychotics, including clozapine.

Importantly, the long-term cumulative mortality risk was lowest for patients treated with clozapine, suggesting that the clinical benefits of using clozapine reduce mortality compared to other antipsychotics and certainly compared to no treatment, despite some possible risks from using clozapine.

Details of the Current Study

The researchers used the entire Finnish population for this population-based study. They first identified all patients who were diagnosed with schizophrenia or schizoaffective disorder between 1972 and 2014 and who were either treated with clozapine or another antipsychotic.

They then looked for cases of new agranulocytosis over a 20-year observation period from 1996 to 2017. They found a total of about 62,000 people diagnosed with schizophrenia or schizoaffective disorder, of which about 14,000 were treated with clozapine and about 48,000 treated with non-clozapine antipsychotics.

Agranulocytosis Incidence and Fatality Rates

In this cohort, 398 individuals were diagnosed with agranulocytosis over the 22-year follow-up:

• 231 individuals treated with clozapine
• 167 individuals treated with non-clozapine antipsychotics

This represents a cumulative incidence of agranulocytosis of:

• 1.37% for clozapine patients
• 0.13% for non-clozapine antipsychotic patients

The agranulocytosis case fatality rate was:

• 2.81 per 10,000 individuals exposed to clozapine
• 0.63 per 10,000 individuals exposed to non-clozapine antipsychotics

Long-Term Agranulocytosis Risk Differences

The long-term agranulocytosis risk is different for clozapine and non-clozapine patients. Patients on clozapine developed agranulocytosis at a higher rate compared to non-clozapine-treated patients.

While the curve for non-clozapine-treated patients basically stays flat over the many years of follow-up, the clozapine agranulocytosis curve continues to creep up, suggesting that over time new cases of agranulocytosis develop in the clozapine group even after the initial period of highest risk that is well-known and well-established in literature.

More than half of the agranulocytosis events in patients treated with clozapine occur during the initial six months and the rest over the remaining follow-up period of up to 22 years.

This suggests two different mechanisms for clozapine-induced agranulocytosis:

• A more acute immune-mediated mechanism
• A more chronic, perhaps toxic mechanism

Discussing Clozapine with Patients

When discussing clozapine with your patients, you need to discuss the agranulocytosis risk, but you can also point out that the absolute risk is low and manageable with monitoring.

Importantly, we must take into account the much higher risk of dying when a serious mental illness goes untreated or is poorly treated.

Clozapine can be lifesaving. However, while some patients might find the new information from this study reassuring, other patients may find the persistence of risk concerning. Ongoing discussion may be needed to get reluctant people on board for a clozapine trial.

Regulatory Considerations in the United States

In the United States, there have been recent advocacy efforts to have the FDA relax the very stringent clozapine monitoring requirements, which is mandatory monthly absolute neutrophil count monitoring after one year of more frequent monitoring for as long as the patient stays on clozapine.

The FDA notes on their website that they are looking into this issue of the need for long-term monitoring, apparently conducting two studies of their own. It remains to be seen how this study will impact the regulatory landscape, as the basic risk-benefit evaluation is a value judgment.

A very conservative view of the study could argue for not changing anything given the persistence of agranulocytosis risk with clozapine. However, such a stance might pose an obstacle to better clozapine utilization in the United States.

Thank you for listening to this Quick Take today. Take care.

Abstract

Long-term persistence of the risk of agranulocytosis with clozapine compared with other antipsychotics: a nationwide cohort and case–control study in Finland

Jose M. Rubio M.D.; John M. Kane M.D.; Antti Tanskanen Ph.D.; Jari Tiihonen M.D.; Heidi Taipale Ph.D.

Background

Agranulocytosis is a life-threatening side-effect of clozapine, the only approved drug for treatment-resistant schizophrenia. The long-term profile of this complication has not yet been well established. Here we aim to describe the risk of clozapine-induced agranulocytosis over the long term.

Methods

We used the entire population of Finland to identify people diagnosed with schizophrenia or schizoaffective disorder between 1972 and 2014 and developed a Kaplan–Meier model of time to diagnosis of agranulocytosis during clozapine versus non-clozapine treatment over a 22-year observation period (1996 to 2017). Next, we developed a nested case–control model for agranulocytosis matching by sex, age, time since diagnosis, and being in the incident cohort on a 1 to 5 ratio. Various durations of use for clozapine and non-clozapine antipsychotic treatment were compared to the modal antipsychotic use duration, deriving adjusted odds ratios (aORs) in a multivariable regression model. Recurrence and lethality rates for clozapine-induced agranulocytosis were described. These data reflect on all individuals with lived experience of schizophrenia in Finland during the study time, although individuals with lived experience were not included in the design of the study.

Findings

We identified 61 769 people with schizophrenia or schizoaffective disorder (14 037 individuals treated with clozapine and 47 732 individuals treated with non-clozapine antipsychotics), with a mean age of 46·67 years (IQR 34·44–57·61), of whom 30 721 (49·7%) were female and 31 048 (50·3%) were male (data on ethnicity not available). Among those, 398 individuals were diagnosed with agranulocytosis (231 individuals treated with clozapine and 167 individuals treated with non-clozapine antipsychotics), representing a cumulative incidence of agranulocytosis for 1·37% (95% CI 0·58–3·16) on clozapine and 0·13% (0·04–0·23) on non-clozapine antipsychotics. In the case (n=398) versus control (n=1987) model, the risk of clozapine-induced agranulocytosis decreased steeply over time from an aOR of 36·01 (95% CI 16·79–77·22) for less than 6 months on clozapine to 4·38 (1·86–10·34) for clozapine use of 54 months or more. Only one of 3559 individuals starting clozapine died because of clozapine-induced agranulocytosis.

Interpretation

The risk of clozapine-induced agranulocytosis decreases steeply over time but might be persistently greater than that of non-clozapine antipsychotics. This long-term risk excess seems small in absolute terms compared with the known magnitude of the advantages of clozapine in relevant outcomes, including life expectancy. Given the widespread underuse of clozapine, relaxing the long-term neutrophil monitoring could favour the advantages of long-term clozapine use, including greater life expectancy, without incurring the intolerable risk of clozapine-induced agranulocytosis.

Funding

Northwell Health and Sigrid Jusèlius Foundation.

Reference

Rubio, J. M.D.; Kane, J. M.D.; Tanskanen, A. Ph.D.; Tiihonen, J. M.D.; Taipale, H. Ph.D. (2024). Long-term persistence of the risk of agranulocytosis with clozapine compared with other antipsychotics: a nationwide cohort and case–control study in Finland. The Lancet Psychiatry. S2215-0366(24)00097-X