01. Clozapine: The Hidden Risks of Ileus and Pneumonia

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Ileus and Pneumonia: Overlooked Clozapine Risks

We will look together at two clozapine side effects, specifically bowel obstruction or ileus and pneumonia, that clinicians may not monitor as diligently as they monitor agranulocytosis.

There will be an important clinical message here in this Quick Take, which I’m willing to give away at the beginning right now.

There is more to clozapine side effects than agranulocytosis, which is clozapine’s most feared side effect, but we ignore other side effects at our patient’s peril, namely, ileus and pneumonia.

Finnish Study Reveals Surprising Findings

Let me explain by looking at a cohort study published in the American Journal of Psychiatry in October of ’24, with the first author being Juulia Partanen from Helsinki, Finland.

This study is one of those legendary longitudinal registry-based studies from Scandinavia where large numbers of people, sometimes a whole population, are included and followed up for many, many years, sometimes even decades.

This population-based work can be done in Scandinavia because they have excellent national public health services and records, where data are systematically collected and tracked in various databases that can be cross-referenced across registries.

In this case, Partanen and colleagues had access to longitudinal data from the so-called FinnGen Biobank, FinnGen Biobank Project that included 2659 participants who had a diagnosis of schizophrenia and who had received clozapine.

The strength of this dataset is not just the large number of clozapine patients but that the follow-up period was long, up to 25 years, with a median follow-up time after clozapine initiation of 12.7 years. The median duration of clozapine use in this cohort was 8.4 years.

Clozapine Linked to Multiple Diseases

They identified 27 in over 2000 diseases that were enriched in clozapine users over their lifetime compared to other groups of people with schizophrenia not on clozapine.

They then used hierarchical clustering to group these 27 diseases with a higher lifetime burden for clozapine patients. Here they are:

• Gastrointestinal hypomotility
• Seizures
• Pneumonia and other acute respiratory tract infections
• Tachycardia
• Then, there was a heterogeneous group that included diabetes and neutropenia.

The most concerning finding was a high adverse side effect burden of ileus and pneumonia, with a cumulative incidence of around 5.3% for ileus and 29.5% for pneumonia, with an increased risk of death.

The odds’ ratio for mortality was 4.5 for ileus and 2.8 for pneumonia.

There were a host of other findings in this dataset, such as an increased rate of seizures with age and an increased risk of almost all side effects with clozapine dose.

ANC Monitoring Validated, Genetic Links Found

They also identified neutropenia that led to clozapine discontinuation, which is almost reassuring since it suggests that the data shows its face validity.

Also, our ANC monitoring is at least an effective strategy to reduce mortality from agranulocytosis, even though there may be discussions on how stringent the ANC monitoring has to be.

Finally, since this was a genetic study, it included a pharmacogenetic component. The researchers found some associations between reduced cytochrome P450, 2C19, and 1A2 activity and a higher risk of pneumonia.

This may be important to consider in patients who develop fever or pulmonary symptoms, as inflammatory cytokines block 1A2 and increase clozapine levels. Reducing the clozapine level in acutely ill patients who are admitted to a medical hospital may be a critical intervention to avoid very high clozapine levels and reduce pneumonia lethality.

Study Findings Mirror Clinical Experience

The study concludes “that clozapine-induced ileus and pneumonia were notably more frequent than has previously been reported and were associated with increased mortality.”

Let me augment this statement by saying that the results of this study match up very well with my own clinical experience.

We have a very large clozapine clinic in our hospital, and I have prescribed clozapine to hundreds of patients for over two decades.

If I look back, I would say that the number of cases of agranulocytosis has been very low.

On the other hand, each year, our clinic gets a few calls from the surgical floor of our general hospital that one of our patients on clozapine was admitted with an ileus despite our best efforts to manage constipation proactively.

Constipation may sound like a nuisance side effect, but it puts people at risk for bowel obstruction, just as the study confirms.

Clozapine causes what has been called “slow gut” in essentially every patient on clozapine, and that self-report of constipation is not sensitive at all.

For that reason, in our clozapine clinic, we proactively manage constipation aggressively with a scheduled stool softener like docusate and a weekly stimulant like senna for everyone, but also stepping up management to a more aggressive bowel regimen with a low threshold when clinically indicated.

Despite our best efforts, we continue to have people who present with ileus. With regard to pneumonia, I, unfortunately, recall quite a few patients with serious and recurrent aspiration pneumonia in our patient cohort, and I do recall patients who died from overwhelming pulmonary infections.

My clinical experience really maps to the research findings from this cohort study.

Key Takeaways for Clozapine Prescribers

When you prescribe clozapine, you and your clinic must develop strategies to track and proactively manage at least two other things as diligently as you track your ANCs.

• Constipation, which could lead to life-threatening ileus.
• Sialorrhea, which may lead to aspiration pneumonia and death.

You may even want to become a vaccine ambassador to ensure your patients receive their recommended vaccinations against influenza, pneumonia, COVID-19, and respiratory syncytial virus or RSV.

A new RSV vaccine for adults was just approved in the US. Attention to these issues may pay off for your own clozapine patients, not just by improving their quality of life, but by actually saving their lives.

Abstract

High Burden of Ileus and Pneumonia in Clozapine-Treated Individuals With Schizophrenia: A Finnish 25-Year Follow-Up Register Study

Juulia J. Partanen, M.D., Paavo Häppölä, M.D., Anders Kämpe, M.D., Ari Ahola-Olli, M.D., Anni Hellsten, M.D., Susanna M. Rask, M.D., Willehard Haaki, M.D., Jarmo Hietala, M.D., Olli Kampman, M.D., Jari Tiihonen, M.D., Antti J Tanskanen, M.D., FinnGen, M.D., SUPER-Finland; Mark J. Daly, M.D., Samuli Ripatti, M.D., Aarno Palotie, M.D., Heidi Taipale, M.D., Markku Lähteenvuo, M.D., Jukka T. Koskela, M.D.

Objective: The authors used longitudinal biobank data with up to 25 years of follow-up on over 2,600 clozapine users to derive reliable estimates of the real-world burden of clozapine adverse drug events (ADEs).

Methods: A total of 2,659 participants in the FinnGen biobank project had a schizophrenia diagnosis and clozapine purchases with longitudinal electronic health record follow-up for up to 25 years after clozapine initiation. Diseases and health-related events enriched during clozapine use were identified, adjusting for disease severity. The incidence and recurrence of ADEs over years of clozapine use, their effect on clozapine discontinuation and deaths, and their pharmacogenetics were studied.

Results: Median follow-up time after clozapine initiation was 12.7 years. Across 2,157 diseases and health-related events, 27 were enriched during clozapine use, falling into five disease categories: gastrointestinal hypomotility, seizures, pneumonia, other acute respiratory tract infections, and tachycardia, along with a heterogeneous group including neutropenia and type 2 diabetes, among others. Cumulative incidence estimates for ileus (severe gastrointestinal hypomotility) and pneumonia were 5.3% and 29.5%, respectively, 20 years after clozapine initiation. Both events were significantly associated with increased mortality among clozapine users (ileus: odds ratio=4.5; pneumonia: odds ratio=2.8). Decreased genotype-predicted CYP2C19 and CYP1A2 activities were associated with higher pneumonia risk.

Conclusions: Clozapine-induced ileus and pneumonia were notably more frequent than has previously been reported and were associated with increased mortality. Two CYP genes influenced pneumonia risk. Pneumonia and ileus call for improved utilization of available preventive measures.

Keywords: Adverse Drug Event; Antipsychotics; Clozapine; Cytochrome P450 (CYP) Enzymes; Epidemiology; Schizophrenia Spectrum and Other Psychotic Disorders.

Reference

Partanen, J. M.D., Häppölä, P. M.D., Kämpe, A. M.D., Ahola-Olli, A. M.D., Hellsten, A. M.D., Rask, S. M.D., Haaki, W. M.D., Hietala, J. M.D., Kampman, O. M.D., Tiihonen, J. M.D., Tanskanen, A. M.D., FinnGen, M.D., SUPER-Finland; Daly, M. M.D., Ripatti, S. M.D., Palotie, A. M.D., Taipale, H. M.D., Lähteenvuo, M. M.D., Koskela, J. M.D. (2024). 

High Burden of Ileus and Pneumonia in Clozapine-Treated Individuals With Schizophrenia: A Finnish 25-Year Follow-Up Register Study

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American Journals of Psychiatry 1;181

(10):879-892.