Higher cancer risk for those on clozapine

Researchers at Karolinska Institutet in Sweden have found that the commonly used antipsychotic clozapine increases the risk of some cancers, including leukemia and lymphoma. Their study, published in a top-ranked journal Psychiatry lancetshows that patients taking clozapine have a much higher risk of developing these tumors than similar patients taking other antipsychotic drugs.

The risk was dose-dependent, meaning that if you take the drug at a higher dose and for a longer time, you’re at a higher risk.

The cumulative dose-dependent increase in odds was about 2.7 times greater for clozapine than for other antipsychotics after long-term exposure, the researchers write.

They add that the absolute risk is small, with 0.7 percent of clozapine-treated patients developing this type of cancer in the long term. However, it should be noted that the risk is much higher with clozapine than with other antipsychotic drugs.

Clozapine has been the subject of controversy since the 1970s. Advocates tout it as the most effective drug for treating psychosis and write that it reduces suicide in people with schizophrenia, while acknowledging that the drug caused an agranulocytosis epidemic in Finland in 1975, which resulted in the drug not receiving FDA approval until 1989 (with caveat to routinely test patients for agranulocytosis). This condition, which occurs in about 0.8% of clozapine users, can be fatal.

The drug also has a number of other known adverse effects in addition to the usual harms of antipsychotics (eg, weight gain, diabetes, central nervous system damage, neuroleptic malignant syndrome). Pneumonia may be one of the more prevalent dangers of clozapine. Other harms of clozapine include heart problems, stuttering, and gastrointestinal problems. About a quarter of those treated with clozapine develop obsessive-compulsive disorder after using the drug. In clinical trials, 16% of participants had to discontinue the drug due to serious adverse effects.

Proponents argue it’s the only drug known to prevent suicide in people with schizophrenia, so it’s worth it. However, some studies have found that the drug Not prevent suicide attempts or deaths by suicide. A 2003 study, commonly cited as evidence that the drug reduces suicide, found that fewer people had suicidal thoughts on clozapine than on other antipsychotics, but there was no statistically significant difference in actual deaths from suicide (in fact, in that studio, Moreover people who died by suicide with clozapine than with other antipsychotics).

We can now add another to the long list of risks with clozapine treatment: cancers such as leukemia, multiple myeloma and lymphomas. The researchers note that the idea that clozapine causes cancer is not new, as previous studies have also found this finding. However, the current study provides the clearest evidence and supports the idea that this link is causal.

Data were collected nationwide and prospectively between 2000 and 2017 in Finland, where approximately 20% of those taking an antipsychotic are taking clozapine. The study included the long-term follow-up of every patient diagnosed with schizophrenia in the country.

The researchers conducted a case-control study comparing 375 patients who developed cancers of the blood and lymphatic system after being treated for schizophrenia with 3734 people who were diagnosed with schizophrenia but did not develop cancer.

The researchers provided adjusted odds ratios for the increased rate of cancers, finding that the greatest risk was for lymphomas:

The cumulative dose-dependent increase in odds was approximately 2.7-fold greater for clozapine (aOR 335) than for other antipsychotics (aOR 125) after long-term exposure greater than 5 years or 5000 [dose equivalents]. The highest odds increase was observed for lymphomas (aOR 406 per 5000 [dose equivalents] exposure).

Regardless of their findings, the researchers write that they explicitly want to increase clozapine use:

To ensure wider access to clozapine therapy, which is the most effective antipsychotic drug, our findings suggest that patients and healthcare professionals should be informed about the early signs of hematologic malignancies, as they are currently encouraged to monitor for early signs of agranulocytosis.

They add: This study provides important new information on the benefit-risk balance of clozapine treatment. However, the mortality benefits of clozapine treatment continue to outweigh the risks. In this cohort, clozapine use was associated with lower all-cause mortality than all other commonly used antipsychotics.

The researchers reported the following financial conflicts of interest: JT, HT, and AT participated in research projects funded by grants from Janssen-Cilag and Eli Lilly at their work institution. JT has served as a consultant or advisor to or received honoraria from: Eli Lilly, Evidera, Janssen-Cilag, Lundbeck, Orion, Otsuka, Mediuutiset, Sidera and Sunovion. JSB is supported by a National Health and Medical Research Council (NHMRC) Boosting Dementia Research Leadership Fellowship and has received grants or advisory funds from NHMRC, the Government of Victoria’s Department of Health and Human Services, Dementia Australia Research Foundation, Yulgilbar Foundation, Aged Care Quality and Safety Commission, Dementia Center for Research Collaboration, Pharmaceutical Society of Australia, GlaxoSmithKline Supported Studies Programme, Amgen and various aged care provider organizations not related to this work. All grants and consultancy funds have been paid to the employer organisation. HT communicates the personal expenses of Janssen-Cilag and Otsuka. All other authors declare no competing interests.

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Tiihonen, J., Tanskanen, A., Bell, JS, Dawson, JL, Kataja, V., & Taipale, H. (2022). Long-term treatment with clozapine and other antipsychotic drugs and the risk of hematologic malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland. Lancet psychiatry, 9, 35362. https://doi.org/10.1016/S2215-0366(22)00044-X (Link)