1 Danish Cancer Society, Institute of Cancer Epidemiology, DK-2100 Copenhagen, Denmark.
2 National Center for Register-based Research, Aarhus University, DK-8000 Aarhus, Denmark.
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ABSTRACT |
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cohort studies; depression; neoplasms; registries
Abbreviations: CI, confidence interval; ICD-8, International Classification of Diseases, Eighth Revision; SIR, standardized incidence ratio
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INTRODUCTION |
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A number of longitudinal epidemiologic studies have been conducted to investigate a possible association. Some of these studies have shown evidence of an increased incidence of cancer in depressed persons (1117
), and some have shown no association (18
22
). The evidence is difficult to interpret, since diverse psychometric scales have been used to define depression, and only some of the cohort studies in the literature have been large enough to evaluate the risk of site-specific cancers. In a nationwide, population-based, long-term follow-up study in Denmark, we investigated the risks of all cancers and of site-specific cancers among patients with depressiondefined as persons admitted to a hospital with a diagnosis of a psychiatric affective disorderusing register-based data for a 25-year period.
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MATERIALS AND METHODS |
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We identified 447,475 hospital admissions for 95,144 persons with diagnoses of affective disorders between April 1, 1969, and December 31, 1993. The diagnoses included in the present study were categorized into four ordinal levels (table 1) according to type of psychopathology. This classification was used in a previous study, but we modified it to include only affective disorders (22). Levels 1, 2, and 3 represent psychotic disorders, and level 4 covers neurotic disorders.
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Follow-up for cancer began on the date of the first recorded admission for depression and ended on the date of cancer (other than nonmelanoma skin cancer) diagnosis (n = 8,512), death (n = 29,208), schizophrenia diagnosis (n = 1,948), or December 31, 1995 (n = 49,823), whichever came first. The first registered diagnoses were allocated to one of the four ordinal levels (table 1), and persons with these diagnoses contributed person-years to these levels until they were readmitted with a diagnosis allocated to a lower level; they contributed person-years at the new level from that date onward. However, if a patient was readmitted with the same diagnosis or a diagnosis allocated to a higher level, he or she remained at the initial diagnostic level. Patients readmitted with a diagnosis of schizophrenia were censored for that diagnosis from the date of readmission onward.
The numbers of cases of cancer observed among individuals hospitalized with depression were compared with those expected on the basis of the age-, sex-, and calendar year-specific incidence rates of first primary cancers in Denmark. Nonmelanoma skin cancer was not considered to be a first primary cancer, and any cancer occurring subsequently was counted as the first primary cancer. The standardized incidence ratio (SIR), taken as the ratio of the observed number of cancer cases to the expected number, was used as a measure of relative risk, and 95 percent confidence intervals were calculated assuming a Poisson distribution of the observed number of cancers (27). SIRs were calculated for all types of cancer combined, for tobacco-related cancers combined (cancers of the buccal cavity, esophagus, pancreas, larynx, lung, kidney, and urinary bladder (28
)), and for a number of site-specific cancers. Furthermore, data for the first year of follow-up were analyzed separately to avoid problems in ascertaining the temporality of disease.
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RESULTS |
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All four groups had a substantially increased risk of brain cancer during the first year of follow-up, with SIRs ranging from 2.5 for dysthymic patients to 4.5 for patients with reactive depression. The risk of brain cancer among patients with bipolar psychosis was increased nearly three times, but not significantly so. None of the groups showed an increased risk of brain cancer after more than 1 year of follow-up. Tobacco-associated cancers and brain cancer accounted for approximately 44 percent of the 106 excess cases of cancer observed in the cohort during the first year of follow-up.
Table 4 shows cancer risks after more than 1 year of follow-up, by site, for the combined diagnostic groups of bipolar or unipolar psychosis and reactive depression or dysthymia, since the cancer patterns were similar in the combined entities. Of the tobacco-associated cancers, the risk of kidney cancer did not reach significance in patients with reactive depression or dysthymia (SIR = 1.19, 95 percent CI: 0.97, 1.45). No deviation from unity was observed for non-Hodgkin's lymphoma in any of the diagnostic groups. A decreased risk of rectal cancer was found for both combined groups (SIR = 0.79 for bi- or unipolar psychosis and SIR = 0.83 for reactive depression or dysthymia). A similar pattern was found for cervical cancer, with a reduction in risk of 1930 percent. Risks were increased for colon cancer (SIR = 1.16) and nonmelanoma skin cancer (SIR = 1.10) among patients with reactive depression and dysthymia, who also had a significantly reduced risk of malignant melanoma (SIR = 0.70).
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DISCUSSION |
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Our study had several advantages. It was a population-based, nationwide cohort study with more than 1 million person-years of follow-up. The size of the study is reflected in the relatively narrow confidence intervals for the risks of site-specific cancers. Reporting of cases to the Danish Psychiatric Central Register is nationwide, and the register covers all inpatient psychiatric facilities in Denmark. Use of the unique 10-digit personal identification number assigned to everyone in Denmark made it possible to eliminate loss to follow-up and incorrect linkage of information. The diagnostic criteria for affective disorders remained unchanged and were considered to be valid throughout the study period (29).
Our cohort did not include all Danes with depression, since it excluded persons with unrecognized disease and those being treated in general medical practices or as outpatients. In addition, the number of beds in the psychiatric hospital system was reduced by more than 50 percent during the study period; accordingly, the proportion of patients (especially dysthymic patients) admitted to psychiatric hospitals decreased considerably. Of course, this could have led to attenuation of any effect of depression on cancer risk, since all persons with depression, regardless of whether they were admitted to a hospital, were included in the background rates. In a previous study, we observed no increased risk of cancer (except for non-Hodgkin's lymphoma) in a large population-based cohort of users of antidepressive medication when we excluded the first year of follow-up (30). Only 13 percent of that cohort had ever been admitted to a hospital for psychiatric inpatient treatment. This supports the conclusion that treatment of depression outside of a hospital did not explain our general finding of no association between affective disorders and cancer in the present study. We included bipolar and unipolar psychoses in our definition of depression, although these disorders have not previously been associated with cancer risk, in order to cover the full spectrum of affective disorders. Our definition of depression probably covered only more severe cases of depression with symptoms that exceeded the threshold for hospitalization. This would have limited our ability to generalize our findings to all persons with depression, but it secured a certain "exposure" level.
The Danish Cancer Registry is nationwide and population-based; practically all cases of cancer occurring in Denmark since 1943 have been reported to the registry (31). To avoid selective inclusion of patients with symptoms resembling depression that were actually due to unrecognized cancer, we separately analyzed data for the first year of follow-up after first admission for an affective disorder. The finding of an increased risk of brain cancer among patients with all levels of psychopathology strongly supports our suspicion that such selection occurred. The increased risk of cancer in general and of brain cancer in particular at first admission for depression underlines the importance of considering physical disease as a possible differential diagnosis for patients with depressive symptoms and points to the challenge of distinguishing between depression and the behavioral effects of organic pathology. Further selection would occur if persons with a previous diagnosis of cancer and an increased risk of developing a second cancer also had a greater risk of being admitted to a hospital with depression. Such selection was avoided in this study, since we excluded all patients with a previous cancer from the cohort and excluded prevalent cases from the background population when calculating the SIRs.
To the best of our knowledge, only one previous cohort study has included patients with a psychiatric diagnosis of depression in assessing overall cancer risk. Among 923 depressed inpatients, overall cancer risk was significantly increased when compared with that of a cohort of 143,573 persons followed for up to 19 years, when the first 2 years of follow-up were excluded from the analysis (n = 63; SIR = 1.38, 95 percent CI: 1.06, 1.76) (14). Most patients in that study had a diagnosis of neurotic depression (83 percent); however, analyses of site-specific cancers revealed no increased risk of tobacco-associated cancers, and most of the excess risk was found to be due to cancers of the breast, endometrium, or skin. Thus, even though the findings are in line with our observation of an overall increased risk in the group of patients with dysthymia, which is equivalent to neurotic depression, the distribution of sites for which there was an increased risk is different.
The authors of other prospective studies assessed depression "psychometrically." In a cohort of 2,018 middle-aged men followed for 20 years, depressed mood at baseline was associated with an increased incidence of all cancers during the first 10 years of follow-up (11). Six subsequent cohort studies of population-based samples comprising 1,5296,913 subjects followed for 1017 years did not confirm an association with cancer in general (12
, 13
, 16
, 18
, 20
, 21
). Only some of these studies provided information on site-specific cancers, including excess risks of lung cancer (12
, 18
) and of smoking-related cancers combined (13
). However, a study of 4,825 persons aged 71 years or older who had been assessed as having depressed mood three times over a 6-year period before the start of follow-up (average, 3.8 years) found an adjusted hazard ratio for all cancers of 1.88 (95 percent CI: 1.13, 3.14) (15
). In that study, the analyses of site-specific cancers revealed no predominant association with tobacco-related cancers. The short follow-up period, the inclusion of data for the first year in the analyses, and the very limited age range are obvious limitations of the study. Therefore, the evidence for an increased risk of all cancers, unaffected by lack of statistical strength, confounding, or bias, must be considered weak. Our findings indicate an excess risk of site-specific cancers, mostly those with a known association with smoking, rather than a generalized effect on cancer risk among depressed patients.
We found an increased risk of smoking-associated cancers among patients hospitalized with reactive depression and dysthymic disorders that remained significant when data were stratified for latency. Two cohort studies in which the risk of smoking-associated cancers was estimated among persons psychometrically found to be depressed suggested that depression modifies the effect of smoking on cancer risk (12, 13
); however, since smoking is a strong risk factor for cancer and adjustment was made using broad categories of smoking, the possibility of residual confounding due to inadequate control for smoking remains in both of those studies. Although a causal relation between depression and smoking-associated cancers cannot be excluded on the basis of our results, the magnitude of the association more likely reflects an increased prevalence of smoking among depressed persons (8
, 9
). Alcohol is an established risk factor for some of the smoking-associated cancers (cancers of the buccal cavity, larynx, and esophagus) (32
). In our study, as many as 17 percent of patients had been admitted with an alcohol-related psychiatric disorder, and the elevated risk observed in all diagnostic categories for esophageal cancer supports the notion that an increased alcohol intake might have contributed to the observed increased risk of tobacco-associated cancers. This conclusion is further supported by the insignificantly increased risk of liver cancer among patients with reactive depression and dysthymia. Both tobacco smoking and alcohol intake can be regarded as confounding factors in the possible association between depression and cancer. Depression may cause an individual to smoke more and/or to drink more alcohol and thereby indirectly lead to an increased risk of cancer. Our data do not answer this question; however, our findings do call attention to a possible link between depression, smoking, and alcohol intake.
No significantly increased risks of tobacco-associated cancers were seen in the groups of patients with unipolar or bipolar manic depression, despite the fact that patients with bipolar disorders have higher rates of smoking than patients with major affective disorders, anxiety disorders, and personality disorders (8). This observation may be due to the difficulties of diagnosing physical illness in psychotic patients, who have paramount mental symptoms and altered behavior during acute phases of their illness. An alternative explanation that has been proposed for the low incidence of cancer in schizophrenic patients is that neuroleptic medications have an antineoplastic effect (33
). Many hospital patients admitted with bipolar disorders are treated with neuroleptic agents, and these compounds may affect their risks of smoking-associated cancers.
In studies of cancer incidence among immune-suppressed subjects, non-Hodgkin's lymphoma, cervical cancer, and various types of skin cancers have been found at increased rates (46
). In the present study, which was restricted to hospitalized patients, we found no deviation in the risk of non-Hodgkin's lymphoma in any diagnostic groups. Antidepressant medications may also affect cancer risk by acting on the immune system, thus representing a possible confounder in the proposed relation between depression and cancer (34
). In a population-based cohort study, an increased risk of non-Hodgkin's lymphoma was observed in long-term users of tricyclic and tetracyclic antidepressants (SIR = 2.5, 95 percent CI: 1.4, 4.2) (30
), which supports the possibility of an etiologic role of antidepressants independent of depression. In the present study, we had no information on patients' use of antidepressive medication; however, our findings do not indicate an excess risk of immune-related cancers among depressed persons.
There seemed to be a generally decreased risk of cervical cancer in this study. This might be explained by a reduced risk of human papillomavirus infection (35) due to the negative effect of depression on sexual activity. To our knowledge, the general tendency toward a reduced risk of rectal cancer in all groups has not been described previously. This finding is not easily explained by current knowledge of the risk factors for this cancer, and the possibility of decreased surveillance in this cohort should be considered. An increased risk of colon cancer was seen in the reactive depressed patients and an increased risk of nonmelanoma skin cancer was seen in the dysthymic patients, whereas the risk of cutaneous melanoma was reduced in the latter group of patients. These results, observed in single diagnostic groups, could be chance findings in view of the large number of statistical analyses performed.
In conclusion, our study provides no support for the hypothesis that depression increases risk of cancer. The increased risks observed in our study can probably be ascribed to behavioral factors, such as increased tobacco smoking and alcohol consumption by patients suffering from affective disorders. In addition, the increased risk of cancer, especially brain cancer, during the first year of follow-up might have been due mainly to reverse causality. The lack of an association between depression and cancer is important and encouraging, but our results call attention to the health effects of the unfortunate distribution of lifestyle factors among these patients.
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ACKNOWLEDGMENTS |
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The authors thank statistician Lars Thomassen for computing assistance.
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NOTES |
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REFERENCES |
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