Researchers at the Karolinska Institutet in Sweden have found that the commonly used antipsychotic clozapine increases the risk of certain cancers, including leukemia and lymphoma. Their study, published in top-tier journal Lancet Psychiatry, demonstrates that patients taking clozapine are at much higher risk of developing these cancers 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 are at higher risk.
“The cumulative dose-dependent increase in odds was about 2.7 times higher for clozapine than for other antipsychotics after long-term exposure,” the researchers write.
They add that the absolute risk is small, with 0.7% of patients on clozapine developing this type of cancer over the long-term. However, it is notable that the risk is so much higher with clozapine than with other antipsychotic drugs.
Clozapine has been the subject of controversy since the 1970s. Proponents tout it as the most effective drug for treating psychosis and write that it decreases suicide in people with schizophrenia, even while acknowledging that the drug caused an “epidemic” of agranulocytosis in Finland in 1975, which led to the drug not receiving FDA approval until 1989 (with a warning to test patients regularly for agranulocytosis). That condition, which occurs in about 0.8% of those who use clozapine, can be fatal.
The drug also has a number of other known harmful effects, in addition to the usual harms of antipsychotics (e.g., 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 severe adverse effects.
Proponents argue that it is the only drug known to prevent suicide in people with schizophrenia, so these risks are worth it. However, some studies have found that the drug does 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—compared with other antipsychotics—but there was no statistically significant difference in terms of actual deaths by suicide (indeed, in that study, more people died by suicide on clozapine than on other antipsychotics).
Now, we can add another to the long list of risks with clozapine treatment: cancers like 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 result. However, the current study provides the clearest evidence and supports the notion that this link is causal.
The data was country-wide and prospectively gathered between 2000 and 2017 in Finland, where about 20% of those on an antipsychotic are taking clozapine. The study included long-term follow-up of every patient diagnosed with schizophrenia in the country.
The researchers conducted a case-control study, comparing 375 patients who had developed blood and lymph system cancers after being treated for schizophrenia to 3734 people who had a schizophrenia diagnosis but did not develop cancer.
The researchers give the adjusted odds ratios for the increased rate of cancers, finding that the highest increased risk was for lymphomas:
“The cumulative dose-dependent increase in odds was about 2.7-times higher for clozapine (aOR 3·35) than for other antipsychotics (aOR 1·25) after long-term exposure of more than 5 years or 5000 [dose equivalents]. The highest increase in odds was observed for lymphomas (aOR 4·06 for ≥5000 [dose equivalents] exposure).”
No matter their findings, the researchers write that they explicitly want to increase clozapine use:
“To ensure a wider access to clozapine therapy, which is the most effective antipsychotic drug, our results suggest that patients and caregivers should be informed about early signs of haematological malignancies, just as they are currently encouraged to monitor early signs of agranulocytosis.”
They add, “This study provides important new information about the benefit-to-risk ratio 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 were all other commonly used antipsychotics.”
The researchers reported the following financial conflicts of interest: JT, HT, and AT have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their employing institution. JT has been a consultant or advisor to or has 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 grant funding or consulting funds from the NHMRC, Victorian Government Department of Health and Human Services, Dementia Australia Research Foundation, Yulgilbar Foundation, Aged Care Quality and Safety Commission, Dementia Centre for Research Collaboration, Pharmaceutical Society of Australia, GlaxoSmithKline Supported Studies Programme, Amgen, and several aged care provider organisations unrelated to this work. All grants and consulting funds were paid to the employing institution. HT reports personal fees from Janssen-Cilag and Otsuka. All other authors declare no competing interests.
Tiihonen, J., Tanskanen, A., Bell, J. S., Dawson, J. L., Kataja, V., & Taipale, H. (2022). Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland. Lancet Psychiatry, 9, 353–62. https://doi.org/10.1016/S2215-0366(22)00044-X (Link)