Patients with schizophrenia were more likely to die younger (by 8 years) and have a shorter duration between time of diagnosis and time of death.
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Patients with schizophrenia often have worse outcomes than their peers without the diagnosis. How you can support your patient in ensuring a better cancer prognosis?
SPECIAL REPORT: PSYCHO-ONCOLOGY PART I
There was a consensus in the old psychiatric literature that cancer was rare in patients with psychotic illnesses such as schizophrenia, as noted in an 1891 article1 published in what is now the British Journal of Psychiatry. Since many researchers at the end of 19th century believed that cancer was a disease brought on by civilization (largely caused by the resultant stress), this observation surprised early researchers, who thought cancer would be more rather than less prevalent in the context of mental illness and its related stresses.
The association of cancer and schizophrenia changed over time. Early studies were based on the ratio of cancer deaths to total deaths in a given population. These studies concluded that patients with psychosis showed a significantly decreased incidence of cancer. Later investigators decided that this conclusion was unwarranted because mortality from other causes (tuberculosis being the main culprit at the time) was higher in patients with psychiatric disorders than in the population at large. Thus, cancer mortality being comparatively low was merely an illusion.2 Later still, researchers realized that important factors such as age, sex, type of cancer, and medication use should be considered before meaningful results could emerge.
For the most part, current thinking is that mortality from cancer is higher in schizophrenia than in the general population, but the actual incidence of most cancers is approximately the same.3 This, however, does not apply to all cancers. For example, data have shown that patients with schizophrenia have a higher rate of breast cancer and a lower rate of melanoma and prostate cancer than controls. High incidence of breast cancer may be due to such factors as low rates of parity and breast feeding in women with schizophrenia, high incidence of smoking, hyperprolactinemia, and adiposity secondary to antipsychotic medication.4
There is also speculation that genetic links may exist between the 2 diseases.5,6 Similarly, the low incidence of melanoma may be explained by the main environmental risk for this cancer (ie, sun exposure). Individuals with schizophrenia live their lives relatively unexposed to sun, as shown by the very low vitamin D levels in this population.7,8 The low rate of prostate cancer is attributed to yet other reasons—reduced sexual activity and hyperprolactinemia induced by antipsychotic drugs.9 Inexplicably, the rates of lung cancer in schizophrenia are not raised despite the fact that patients with psychiatric disorders are very often heavy smokers.10
Altogether, cancer rates in schizophrenia appear to be lower than might be expected given the serious risk factors (ie, smoking and adiposity) found in this population. Two explanations have been advanced—tumor suppressor genes among genes involved in schizophrenia and tumor suppressant effects of antipsychotic medication.11,12 It is always possible, however, that reduced cancer rates in patients with schizophrenia may simply reflect low rates of screening and underdiagnosis as well as premature death (ie, due to tuberculosis and now cardiovascular disease).13
Cancer mortality rates in schizophrenia do not reflect a reduced incidence. They are high, especially for stomach cancer, lung cancer, and breast cancer (Figure).14,15 For example, Bradford and colleagues16 examined the records of almost 35,000 veterans with lung cancer and found that those with a diagnosis of schizophrenia showed significantly poorer survival than their peers.
With respect to breast cancer, a Finnish study that controlled for age, year of cancer diagnosis, and comorbidity found significantly elevated breast cancer mortality in patients with severe mental illness.17 The researchers thought the elevation might be partly explained by cancer stage at presentation.
The discrepancy between roughly equal incidence and higher mortality is probably attributable to a variety of factors including patient, doctor, and system factors (Table).18-20 For example, it has been observed that fewer patients with severe mental illness receive chemotherapy or radiation post-mastectomy compared with the general population of patients with breast cancer.17
A 2020 systematic review of all cancer screening (breast, cervix, colon, lung, stomach, ovary, and prostate) publications included information on close to 5 million individuals with and without mental illness.21 The majority were women, and the median quality of all the studies was judged as high. The findings indicated that cancer screening is significantly less frequent in people with mental illness than it is in the general population. According to Howard and colleagues,22 the relative failure of patients with severe mental illness to seek cancer screening were due transportation issues, lack of reminders, and not being familiar with the process. As a result of decreased screening, cancers come to medical attention at relatively later stages and are, therefore, less amenable to treatment. In turn, these cancers are more likely to lead to treatment non-response and early death.
If the stage of presentation were not a confounding factor, would there still be a disparity in cancer care between those with psychotic illness and those without?23 Other considerations play a part, such as enrollment in trials of cancer drugs. Protocols often exclude individuals with schizophrenia on the assumption that they may not be competent to consent or will be unable to adhere to the protocol.24,25 Tests of competency can, of course, be administered prior to consent, so decisional capacity should not be a major drawback.22
Similarly, it is possible that physicians minimize the clinical significance of the complaints from patients with psychotic disorders, attributing such complaints to psychotic phenomena (eg, diagnostic overshadowing).26 This may be due to patients’ communication difficulties and poor recall, but also to mental illness stigma, which is prevalent even among physicians. It has also been reported that patients with schizophrenia have a high pain threshold, so they may not complain until late stages of disease.18 Moreover, patients may have little family encouragement to visit their doctor when symptoms manifest. Patients with psychotic illness may be difficult to treat, not only because of relatively poor adherence to treatment regimens, but also because of extensive comorbidities, namely the high prevalence of obesity, diabetes, and cardiovascular disease. Finally, there may be problems associated with interactions among the various drugs required for the various disorders.22
Outright treatment refusal may also occur, which would necessitate tests of decisional capacity and, if necessary, surrogate consent. The onus is on the psychiatric staff to liaise with non-psychiatric medical practitioners and advocate for their patients.
Disparities have been found even with end-of-life care between patients with schizophrenia and the general population.27 Such a comparison was made between 2500 patients with schizophrenia and 200,000 controls, all of whom had died in hospital as a result of cancer. The researchers also undertook a sub-analysis between the patients with schizophrenia and 10,000 controls matched 1 to 4 in terms of age, sex, and site of the primary cancer. They found that patients with schizophrenia were more likely to die younger (by 8 years) and have a shorter duration between time of diagnosis and time of death. Patients with schizophrenia were more likely than controls to receive palliative care in the last month of life but less likely to receive chemotherapy, surgery, imaging investigations, endoscopies, or blood transfusions.
A potential reason for the disparity is the increased comorbidities associated with patients who have schizophrenia. There was a large number of lung cancer deaths among the participants in this study, so another potential reason for the discrepancies was the high rate of smoking in schizophrenia populations. Interestingly, the patients with schizophrenia were less likely to have recorded metastases at the time of death than their matched controls, suggesting to the researchers that they had undergone fewer diagnostic explorations or had died of their primary cancer prior to the development of metastases, perhaps because of a delay in treatment initiation. Such a delay may be due to the fact that patients with schizophrenia were less likely than controls to have had family doctors.
Patients with schizophrenia were more likely to die younger (by 8 years) and have a shorter duration between time of diagnosis and time of death.
The results were interpreted cautiously, but the researchers stressed that evident disparities in cancer care exist. They concluded that providing clinical care to an individual with comorbid schizophrenia and cancer requires expertise in both oncology and psychiatry and necessitates training that does not exist at present. It also requires improved coordination of care among the different branches of medicine.27
The issue of antipsychotics and their contribution to the cancer-schizophrenia connection is complicated. On one side are the arguments that antipsychotics predispose to cancer or make treatment less effective than it would be otherwise. On the other side are arguments that antipsychotics have anti-tumor properties.
Similarly, there have been back-and-forth discussions on antipsychotics contributing to mortality in schizophrenia via induced obesity, metabolic problems, and prolactin elevation. Most of this literature deals with the association between schizophrenia and premature death due to cardiovascular causes.13,28
Interesting, a meta-analysis of 20 studies on the relationship between long-term mortality and exposure to antipsychotic medication in patients with schizophrenia showed that patients not taking antipsychotics had a higher mortality than those who did.29 This does not, however, exonerate antipsychotics. Patients not taking antipsychotics may receive inferior medical care, and they may have higher rates of suicide and fatal accidents. This study does not specifically address cancer mortality and the use of antipsychotics.
The controversy about cancer mortality and schizophrenia rages most fiercely around the topic of breast cancer. A critical review by De Hert and colleagues30 found that while a large body of evidence supports the involvement of prolactin in breast carcinogenesis, results of human studies remain equivocal as to the role of antipsychotics-induced hyperprolactinemia either in increasing the risk of cancer or in contributing to high mortality. The researchers concluded that a high incidence of nulliparity, and the prevalence in the schizophrenia population of obesity, diabetes mellitus, and unhealthy behaviors (eg, alcohol dependence, smoking, low physical activity), is of greater relevance to breast cancer mortality than antipsychotics.
At the same time, there is emerging evidence that at least some antipsychotics protect against cancer. Sertindole was found to be effective against breast cancer cell lines, with the suggestion that it might be able to stop breast to brain metastases.31 Other studies have found antipsychotics to be effective treatments for glioblastomas and a wide variety of other malignancies.12,32,33 These studies are thought-provoking, but they need replication.
For the clinician, this brief review recommends close health monitoring of patients with psychotic illness to prevent or treat weight gain and prolactin elevation. Should patients with schizophrenia develop cancer, there are no good reasons to take them off an effective antipsychotic drug regimen. However, drug interactions with chemotherapeutic agents may need to be checked.
More broadly, physicians need to treat patient complaints at face value even when they are communicated in a disorganized way. Decisional competence and ability to follow through on complicated therapeutic protocols should not be based on diagnosis alone; competency screening is important in such cases. To truly address the problem, all patients with schizophrenia should be linked to a primary care physician, psychiatrists and oncologists should develop a common language, and psychiatry should be more firmly integrated with the rest of medicine.
Dr Seeman is Professor Emerita, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. She reports no conflicts of interest concerning the subject matter of this article.
1. Snow H. Cancer in its relations to insanity. J Ment Sci. 1891;37:548-553.
2. Ananth J, Burnstein M. Cancer: less common in psychiatric patients? Psychosom. 1977;18:44-46.
3. Catalá-López F, Suárez-Pinilla M, Suárez-Pinilla P, et al. Inverse and direct cancer comorbidity in people with central nervous system disorders: A meta-analysis of cancer incidence in 577,013 participants of 50 observational studies. Psychother Psychosom. 2014;83:89-105.
4. Kyrgiou M, Kalliala I, Markozannes G, et al. Adiposity and cancer at major anatomical sites: umbrella review of the literature. BMJ. 2017;356:j477.
5. Byrne EM, Ferreira MAR, Xue A, et al. Is Schizophrenia a risk factor for breast cancer? — evidence from genetic data. Schizophr Bull. 2019;45:1251–1256.
6. Kim S, Kim K, Myung W, et al. Two-sample Mendelian randomization study for schizophrenia and breast cancer. Precision Future Med. 2020;4:21-30.
7. Gandini S, Sera F Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure. Eur J Cancer. 2005;41:45-60.
8. Valipour G, Saneei P, Esmaillzadeh A. Serum vitamin D levels in realtion to schizophrenia: a systematic review and meta-analyss of observational studies. J Clin Endocrinol Metabol. 2014;99:3863-3872.
9. Raviv G, Laufer M, Baruch Y, et al. Risk of prostate cancer in patients with schizophrenia. Compr Psychiatry. 2014;55:1639-1642.
10. Zhuo C, Zhuang H, Gao X, et al. Lung cancer incidence in patients with schizophrenia: meta-analysis. Br J Psychiatry. 2019;215:704–711.
11. Zhuo C, Wang D, Zhou C, et al. Double-edged sword of tumour suppressor genes in schizophrenia. Front Mol Neurosci. 2019;12:1.
12. Huang J, Zhao D, Liu Z, et al. Repurposing psychiatric drugs as anti-cancer agents. Cancer Letters. 2018;419:257-265.
13. Seeman MV. Schizophrenia mortality: barriers to progress. Psychiatr Q. 2019;90:553-563.
14. Ajdacic-Gross V, Tschopp A, Bopp M, et al. Cancer comortality patterns in schizophrenia and psychotic disorders: a new methodological approach for unique databases. Int J Meth Psychiatr Res. 2014;23:9-24.
15. Ni L, Wu J, Long Y, et al. Mortality of site-specific cancer in patients with schizophrenia: a systematic review and meta-analysis. BMC Psychiatry. 2019;19:323.
16. Bradford DW, Goulet J, Hunt M, et al. A cohort study of mortality in individuals with and without schizophrenia after diagnosis of lung cancer. J Clin Psychiatry. 2016;77:e1626-e1630.
17. Ahlgrén-Rimpiläinen AJ, Arffman M, Suvisaari J, et al. Excess mortality from breast cancer in female breast cancer patients with severe mental illness. Psychiatry Res. 2020;286:112801.
18. Zhou L, Bi Y, Liang M, et al. A modality-specific dysfunction of pain processing in schizophrenia. Hum Brain Map. 2020;41:1738-1753.
19. Seeman MV. Schizophrenia and cancer: low incidence, high mortality. Res J Oncology. 2017;1:6.
20. Shinden Y, Kijima Y, Hirata M, et al. Clinical characteristics of breast cancer patients with mental disorders. Breast. 2017;36:39-43.
21. Solmi M, Firth J, Miola A, et al. Disparities in cancer screening in people with mental illness across the world versus the general population: prevalence and comparative meta-analysis including 4 717 839 people. Lancet Psychiatry. 2020;7:52–63.
22. Howard LM, Barley EA, Davies E, et al. Cancer diagnosis in people with severe mental illness: practical and ethical issues. Lancet Oncol. 2010;11:797–804.
23. Irwin KE, Henderson DC, Knight HP, et al. Cancer care for individuals with schizophrenia. Cancer. 2014;120:323-334.
24. Humphreys K, Blodgett JC, Weiss Roberts L. The exclusion of people with psychiatric disorders from medical research. J Psychiatr Res. 2015;70:28-32.
25. Irwin KE, Moy B, Fields LE, et al. Expanding access to cancer clinical trials for patients with mental illness. J Clin Oncol. 2019;37:1524–1528.
26. Jones S, Howard L, Thornicroft G. ‘Diagnostic overshadowing’: worse physical health care for people with mental illness. Acta Psychiatr Scand. 2008;118:169–71.
27. Fond G, Salas S, Pauly V, et al. End-of-life care among patients with schizophrenia and cancer: a population-based cohort study from the French national hospital database. Lancet Public Health. 2019;4:e583-e591.
28. Vermeulen J, van Rooijen G, Doedens P, et al. Antipsychotic medication and long-term mortality risk in patients with schizophrenia; a systematic review and meta-analysis. Psychol Med. 2017;47:2217-2228.
29. de Mooij LD, Kikkert M, Theunissen J, et al. Dying too soon: Excess mortality in severe mental illness. Front Psychiatry. 2019;10:855.
30. De Hert M, Peuskens J, Sabbe T, et al. Relationship between prolactin, breast cancer risk, and antipsychotics in patients with schizophrenia: a critical review. Acta Psychiatr Scand. 2016:133: 5-22.
31. Zhang W, Zhang C, Liu F, et al. Antiproliferative activities of the second-generation antipsychotic drug sertindole against breast cancers with a potential application for treatment of breast-to-brain metastases. Sci Rep. 2018;8:15753.
32. Lee JK, Nam DH, Lee J. Repurposing antipsychotics as glioblastoma therapeutics: Potentials and challenges. Oncol Lett. 2016;11:1281-1286.
33. Zhuo C, Xun Z, Hou W, et al. Surprising anticancer activities of psychiatric medications: Old drugs offer new hope for patients with brain cancer. Front Pharmacol. 2019;10:1262.
34. National Cancer Institute. Cancer Disparaties. 2011-2015. https://www.cancer.gov/about-cancer/understanding/disparities. Accessed June 11, 2020.
35. Ji J, Chen X. Incidence of cancer in patients with schizophrenia and their first-degree relatives: a population-based study in Sweden. Schizophr Bull. 2013;39:527-536.