Unit of Healthcare Epidemiology, Department of Public Health, University of Oxford, UK
Department of Health Studies, University of Chicago, Chicago, Illinois, USA
Unit of Healthcare Epidemiology, Department of Public Health, University of Oxford, UK
Correspondence: Professor Michael J.Goldacre, Unit of Health-Care Epidemiology, Department of Public Health, University of Oxford, Old Road Campus, Old Road, Oxford OX3 7LF, UK, Tel: +44 (0)1865 226994; fax: +44 (0) (0)18 1865 226993; e-mail: michael.goldacre{at}dphpc.ox.ac.uk
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ABSTRACT |
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Aims To study cancer incidence in schizophrenia.
Method Cohort analysis of linked hospital and death records was used to compare cancer rates in people with schizophrenia with a reference cohort.
Results We did not find a reduced risk for cancer overall (rate ratio 0.99,95% CI 0.901.08) or for most individual cancers. There was, however, a significantly low rate ratio for skin cancer (0.56,95% CI 0.360.83).
Conclusions We found no evidence that schizophrenia confers protection against cancer in general. Low rates of cancer are consistent with the hypothesis that sun exposure may influence the development of schizophrenia, although other explanations are also possible.
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INTRODUCTION |
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METHOD |
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The schizophrenia cohort was constructed by identifying the first admission to an NHS hospital during the study period, or the first contact with specialist psychiatric services for those in Oxfordshire, for each individual with the condition. A reference cohort was constructed by identifying the first admission for each individual with various medical and surgical conditions (see footnotes to Table 2). This is based on our reference group of conditions, which has been used in other studies of interrelationships between diseases (Goldacre et al, 2000). We searched the database for any subsequent NHS hospital care for, or death from, cancers in these two cohorts. We considered that rates of cancer in the reference cohort would approximate those in the general population of the region while allowing for migration in and out of it (data on migration of individuals were not available).
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Statistical methods
We calculated rates of each cancer based on person-years at risk. We took
date of entry into each cohort as the date of first admission
for schizophrenia or reference condition, and date of exit for
the analysis of each individual cancer as the date of first record of the
cancer, death or 31 March 1999, whichever was the earliest. In comparing the
schizophrenia cohort with the reference cohort, we first calculated rates for
each cancer, standardised by age (in 5-year age groups), gender, calendar year
of first recorded admission and district of residence, taking the combined
schizophrenia and reference cohorts as the standard population. We then
applied the overall rates to the age structure of the individual cohorts of
people with schizophrenia or with the reference conditions. We calculated the
ratio of the standardised rate of occurrence of cancer in the schizophrenia
cohort relative to that in the reference cohort. The confidence interval for
the rate ratio and w2 statistics for its significance were
calculated as described elsewhere (Breslow
& Day, 1987).
We studied the results for each condition in the reference cohort separately, as well as in combination, to ensure that no individual condition disproportionately influenced the expected number of people with subsequent cancer. The people in the reference cohort who underwent appendicectomy or an operation for inguinal hernia or haemorrhoids showed significantly high subsequent admission rates for colorectal cancers. We therefore excluded these conditions from the reference cohort in the study of colorectal cancers, when comparing the schizophrenia and reference cohorts.
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RESULTS |
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The risk ratio for cancer, overall, in people with schizophrenia, compared with the reference cohort, was 0.99 (Table 2). The risk ratio for cancer of the lung was non-significantly raised at 1.18 and that for cancer of the oesophagus was significantly raised at 1.61. No other individual cancer was found to be significantly more common in people with schizophrenia than in the reference cohort. Skin cancer was significantly less common in people with schizophrenia than in others (Table 2). The rate ratio for skin cancer was 0.56 (P=0.004). Malignant melanoma and other skin cancers were, individually, less common in people with schizophrenia than in the reference cohort. The rate ratio for malignant melanoma was particularly low at 0.20 (P=0.02). Cancer of the rectum was significantly lower in the schizophrenia cohort than in the comparison cohort, with a rate ratio of 0.57 (Table 2; P=0.03). Cancer of the colon was lower in the schizophrenia cohort than in the comparison cohort, but the result was not significant (rate ratio 0.72, P=0.06).
The results presented here included patients of all ages when they had their first recorded admission for schizophrenia. We also analysed the data restricting the analyses to people whose first recorded admission for schizophrenia (or reference condition) was between the ages of 15 years and 64 years, reasoning that the identification of schizophrenia and of cancers is less likely to be reliable in the elderly than in the younger population. Apart from lowering statistical power, restriction of the age range in this way made no appreciable difference to the results.
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DISCUSSION |
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Nonetheless, interest in the possible protective effect of schizophrenia persisted. The following three decades yielded a large number of studies (reviewed by Baldwin, 1979), generally of low statistical power, and further studies were published after Baldwins review. For example, Craig & Lin (1981) reported that the risk of lung cancer in people with schizophrenia may be low, despite the fact that high rates of smoking are well documented in patients with the latter disorder (Kelly & McCreadie, 1999). Two large-scale, long-term studies in Denmark showed lower rates of several cancers, including lung cancer, in people with schizophrenia than in the general population (Mortensen, 1989, 1994). The first study followed a cohort of 6168 people with schizophrenia over a period of 27 years by far the most substantial piece of work on this topic to date. It found a significantly reduced incidence of cancer overall in male patients as well as significant reductions in lung cancer and some other smoking-related cancers in both men and women (Mortensen, 1989). It found a small but significant elevation in the risk of breast cancer (rate ratio=1.19). The results were ascribed to the hospital environment experienced by psychiatric patients during the 1950s and 1960s when, it was reported, smoking in the study population was said to have been restricted both by the patients limited means and by regulations against smoking in Danish psychiatric hospitals (Mortensen, 1989). It was considered that a low pregnancy rate and reduced sexual activity could have accounted respectively for the increased risk of breast cancer and the finding of a non-significant reduced risk of cervical cancer among the female patients with schizophrenia (Mortensen, 1989).
A more recent, but less statistically powerful, cohort study was performed in Denmark to determine whether the earlier findings in an institutional environment, with restricted access to tobacco, were replicated in a more modern population of patients (Mortensen, 1994). The risk estimates generated by this study were less stable, since fewer malignancies were observed in the population. As before, cancer incidence overall was reduced in male patients. There was a non-significant reduction in lung cancer in men, based on six cases. The author concluded that the results of this second study did replicate those of the first and suggested that neuroleptic treatment might somehow be protective against cancer in people with schizophrenia (Mortensen, 1994).
Findings in our study
Our findings do not support the hypothesis that people with schizophrenia
have a different overall risk of cancer from that of the general
population.
Cancers of the lung and oesophagus
We did not find that lung cancer occurred less often in people with
schizophrenia than in the general population. We found that the risk of lung
cancer was non-significantly elevated and that the risk of cancer of the
oesophagus was significantly elevated in people with schizophrenia, compared
with the reference cohort. Smoking is the major risk factor for lung cancer
and a high level of alcohol consumption is a risk factor for cancer of the
oesophagus. The elevated rates of cancer of the lung and oesophagus may be
attributable to smoking and alcohol consumption in the population with
schizophrenia. We do not have data on smoking history or alcohol consumption.
The research literature shows that people with schizophrenia are more likely
to smoke than the general population
(Kelly & McCreadie, 1999).
If there were much higher rates of smoking in the population with
schizophrenia studied by us, we might have expected to see higher rates of
lung cancer in these patients than we did. Thus, we cannot rule out the
possibility that schizophrenia does protect against lung cancer to some
extent. Nonetheless, because lung cancer rates in the schizophrenia cohort
were high, our results indicate that it is unlikely that schizophrenia is
associated with a major protective effect against lung cancer, and our results
show no evidence of a general protective effect against other cancers.
Breast cancer
We found no elevation of breast cancer in our schizophrenia cohort, with a
rate ratio of 1.
Colorectal cancer
We found a significantly low rate of rectal cancer. Dietary factors have a
role in the aetiology of colorectal colorectal cancer, and there is evidence
that there are differences in diet between people with schizophrenia and
others (McCreadie, 2003), but
a specific lowering of the risk of colorectal cancer is not a consistent
feature of the literature on schizophrenia and cancer.
Brain tumours
There was no elevation of rates of brain tumours after a first diagnosis of
schizophrenia. This shows that there was no evidence of any significant
misdiagnosis of brain tumours as schizophrenia.
Skin cancer
We found that skin cancer occurred considerably less frequently in patients
with schizophrenia than in the general population. There is not much published
information about schizophrenia and skin cancer. However, a similar finding
was reported from the second Danish recordlinkage study
(Mortensen, 1994). The rate
ratio in that study for malignant melanoma in people with schizophrenia, 0.14,
was similar to our ratio of 0.20. Mortensen
(1994) also reported a
reduction in other skin cancers, similar to our risk estimate. There are
several reasons why skin cancer rates may be lower than expected in people
with schizophrenia. People with schizophrenia may spend less time in the sun
than the general population. They may be less likely to seek medical advice
than others. If doctors are less inclined to treat skin cancer in people with
schizophrenia than in others, people with schizophrenia and skin cancer might
be less likely to be admitted to hospital and therefore be selectively missed
by our study method. Another possible explanation is that our findings might
be due to chance: because we analysed 32 cancers, we would expect to find one
or two statistically significant results by chance alone. However, with a
prior hypothesis from the Danish record-linkage study that a low rate of skin
cancer might be expected (Mortensen,
1994), and a significance level of 1 in 250 (P 0.004) in
our study, we are reluctant to accept chance as the most likely explanation.
The low level of skin cancer is consistent with the hypothesis that sun
exposure, perhaps through its role in vitamin D synthesis, may have a
protective role in the development of schizophrenia. Moskovitz
(1978) suggested that vitamin
D deficiency in the neonate might be a risk factor for the subsequent
development of schizophrenia, and that this might be one explanation for the
well-documented excess of winter births among people with schizophrenia.
McGrath (1999) suggested that
relative vitamin D deficiency could parsimoniously explain
diverse epidemiological features of schizophrenia such as the excess of winter
births in people with schizophrenia and the increased rate of schizophrenia in
dark-skinned migrants to climates with much more limited sunshine. If, in some
people, solar radiation has a protective influence in the interaction of risk
factors that lead to schizophrenia, skin cancer rates could be lower in people
with schizophrenia than in others for that reason. There are other
long-standing linked databases, for example in Scotland
(Kendrick & Clarke, 1993)
and Western Australia (Holman et
al, 1999), that could be used to determine whether the
deficit of skin cancer in people with schizophrenia is a consistent finding.
The methods used by van der Mei et al
(2003), who made physical
measurements of evidence of past skin exposure to solar radiation in people
with multiple sclerosis, could be used to study the skin structure of people
with and without schizophrenia.
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Strengths and weaknesses of the study |
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Implications of our findings |
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication May 18, 2004. Revision received December 7, 2004. Accepted for publication December 14, 2004.
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