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The occurence of cancer in first admitted schizophrenic patients
SCHIZOPHRENIA RESEARCH ELSEVIER
Schizophrenia Research 12 (1994) 185-194
The occurrence of cancer in first admitted schizophrenic patients Preben Bo Mortensen* Institute of Basic Psychiatric Research, Department of Psychiatric Demography, Psychiatric Hospital in Aarhus, K-8240 Risskov, Denmark (Received
1 August
1992; revision received
1 September
1993; accepted
10 September
1993)
Abstract The incidence of cancer was studied in a cohort of all first admitted 9156 patients in Denmark with a diagnosis of schizophrenia in the period 1970-1987. The overall incidence of cancer was reduced particularly in the males. Adjustment for the smoking habits of psychiatric patients enhanced this risk reduction. Fewer than expected had been diagnosed with cancer prior to the first schizophrenia admission. This tendency was limited to the female patients. The reduced cancer incidence was particularly marked for genital cancers, in particular testicular cancer, and skin cancers including malignant melanoma. Breast cancer risk was not increased, thus not substantiating concerns that neuroleptics would increase breast cancer risk through the elevation of serum prolactin levels. Some available evidence in the literature supports the hypothesis of an antineoplastic effect of neuroleptics as an explanation for the low occurrence of cancer in schizophrenic patients. Further large sample studies including an extension of the followup of this cohort are needed to establish the reduced risk of cancer in schizophrenic patients as well as exploring the causes for this reduction. Key words: Cancer incidence;
Smoking
1. Introduction A reduced occurrence of cancer in schizophrenic patients has been reported in the literature throughout most of this century (for reviews see Du Pan and Mtiller, 1977; Baldwin, 1979; Simpson, 1988). A number of methodological problems, however, have hampered especially the early reports, and the issue of whether schizophrenics differ from the general population in terms of cancer risk remains controversial (Fox and Howell, 1974; Harris, 1988). A number of studies of mortality in schizophrenic patients report the cause specific mortality from cancer (e.g. Zilber et al., 1989; Mortensen *Corresponding 0920-9964/94/$7.00
author. 0 1994 Elsevier Science B.V. All rights reserved
SSDZ 0920-9964(94)E0071-2
and Juel, 1990; for a review see Simpson, 1988). However, cancer mortality does not only measure cancer incidence, but also the survival of those who develop cancer, and mortality from other causes may complicate the interpretation of cancer mortality data as indicators of cancer risk. It follows that cancer incidence rather than cancer mortality would be the preferable type of data when studying cancer risk in schizophrenia. A WHO multicenter study addressed this issue and the findings from the Danish study in this collaboration indicated a reduced incidence of some types of cancer (DuPont et al., 1986; Mortensen, 1989). The material in that study consisted of all schizophrenic patients in Danish psychiatric hospitals on a census day in 1957 (Arentsen and Striimgren, 1959), mainly chronic
186
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patients with admissions to mental hospitals that often had lasted several decades. The Japanese study in the same WHO collaboration reported an increased breast cancer risk in young female patients (Nakane and Ohta, 1986), and in a study from Honolulu, Hawaii, in this collaboration female patients of Japanese origin had an increased cancer risk whereas male Japanese patients and Caucasian patients of both sexes did not differ significantly from the general population in terms of cancer risk (Gulbinat et al., 1992). An earlier incidence study reported no difference between schizophrenic patients and the general population (Ehrenteil, 1957). More limited sample size and other methodological issues in these studies, however, made it hard to arrive at firm conclusions. There were indications that tobacco smoking had been very limited in the cohort included in the previous Danish studies (DuPont et al., 1986; Mortensen, 1989) as opposed to what is the case in the present day population of schizophrenic in-patients (Masterson and O’Shea, 1984). However, only one previous study exists in the literature regarding the incidence of cancer in schizophrenic patients treated in the present day psychiatric hospital system (Baldwin, 1980), and in that study, reporting no difference of cancer incidence between schizophrenic patients and the general population, the sample size was not sufficiently large to allow any firm conclusions. The aim of the present study is to describe the incidence of cancer in a total national sample of first admitted schizophrenic patients in order to see whether the previous findings from old long stay patients with limited tobacco smoking can be replicated in the present day population of schizophrenic in-patients. Furthermore it will be attempted to evaluate if cancer occurrence is altered prior to the first schizophrenia admission in those who later develop schizophrenia.
2. Material and methods The material consisted of all 9156 persons, 5658 males and 3498 females, who were first admitted to a Danish psychiatric hospital or department
Research 12 (1994) 185-194
during the period April 1, 1970 to December 31, 1987, and who at least at one admission were diagnosed schizophrenia (ICD-8 295). The aim of the design was to include a sample representing the incident cases of schizophrenia, as opposed to prevalent cases. It was decided, however, not to base the inclusion in the study solely on the diagnosis from the first admission because only approximately half of those who eventually are diagnosed schizophrenia receive this diagnosis at their first psychiatric hospitalization (MunkJorgensen, 1987). The patients were all identified through The Danish Psychiatric Case Register. This nationwide register has been in operation on a computerized basis since 1969, covering all Danish psychiatric in-patient facilities since April 1, 1970 (DuPont, 1983). It was not within the scope of this study to examine the validity of the schizophrenia diagnosis in The Danish Psychiatric Case Register, but in a study of 53 schizophrenic patients from one catchment area selected along the same lines as in this study (Munk-Jorgensen and Mortensen, 1989), 45 of the 53 included patients met DSM-III criteria for schizophrenia, further three patient met these criteria except for the age of onset which was above 45, (and those fulfilled DSM-III-R criteria) and four could not be classified according to DSMIII because of lack of sufficient information in the case records (Munk-Jorgensen, unpublished data). There are no private psychiatric in-patient facilities in Denmark, and the present study population thus represents a total national sample of all first admitted psychiatric in-patients who are diagnosed schizophrenia. Cancer cases were identified through linkage with the nationwide Danish Cancer Registry, which has been in operation since 1947 (Clemmesen, 1965). The unique person identifier (CPR-number) was used as identification of the patient in The Cancer Registry. In this manner a total of 133 patients, 47 males and 86 females, who had developed cancer after their first admission to a psychiatric hospital with the diagnosis of schizophrenia, were identified. The total number and dates of deaths in the study population was known as of the 25.3.1988, through the routine linkage between The Danish Psychiatric Case Register and The Danish Central Person Registry.
P.B. MortensenlSchizophrenia
The relation between cancer risk in schizophrenics and the general Danish population was estimated by calculating the indirectly standardized incidence ratio i.e. by dividing the observed number of cancers with the corresponding expected number given the age-, gender-, and calendar period(1970-72, 1973-77, 1978-82, 1983-88) -specific number of person years in the study population and the corresponding general population cancer incidence rates made available by The Danish Cancer Registry. This calculation is analogous to the calculation of a standardized mortality ratio (SMR). All observations were calculated as starting on the first day of the first admission with a schizophrenia diagnosis and ending by the date of cancer diagnosis, the date of death or by censoring on the 25.3.1988. The calculations were made using the OLVP6 program developed by Juul, ( 1984). The two-tailed p-values are the exact p-values based on the Poisson distribution for the observed number of cancer cases multiplied by two. The cancer occurrence prior to the first schizophrenia admission was assessed by comparing the number of schizophrenic patients who were registered in the Danish Cancer Registry prior to the first day of the first schizophrenia admission, to the expected number of such cases standardized for age and gender. This expected number was calculated on the basis of the age and gender specific number of schizophrenic patients, and the age and gender specific proportion of the general population who had been registered in the Danish Cancer Registry, and who were alive on 1.1.1981 (Danish Cancer Registry 1985). Recent data show that tobacco smoking is more frequent among first admitted psychiatric inpatients than in the general Danish population. In a Danish sample of 163 first admitted psychiatric patients between 18-49 years old, 72.8% of males and 72% of females reported to be smokers (Mors and Sorensen, personal communication). The corresponding age specific figures for the general Danish population in 1987 are 49.6% and 41.5% in males and females respectively (Nielsen et al., 1988). The proportion of heavy smokers (> 15 cigarettes per day) was 53.1% and 43.9% in male and female psychiatric patients respectively. The proportion of heavy cigarettes smokers in the
187
Research I2 (1994) 185-194
general Danish population was 21.6% in males and 15.2% in females (Nielsen et al., 1988). In order to take this difference into account when calculation the expected number of smoking related cancers the relative risks for smokers versus non-smokers reported by Doll and Peto ( 1981) was used. The ‘adjusted’ expected number was calculated using the formula adjusted
expected
number
=
(ax RR+b) cxRR+d x expected
number
where a and b respectively denote the proportion of smokers and non-smokers among psychiatric first admitted patients and c and d respectively denote the corresponding proportions in the general population. RR is the relative risk between smokers and non-smokers for developing specific types of cancer as reported by Doll and Peto, (1981).
3. Results The incidence rate ratio for all cancers combined as well as main groups and selected subgroups of tumor sites are reported in Table 1. Male schizophrenic patients had a significantly reduced incidence of cancer, whereas the reduction in the females was not statistically significant. No type of cancer occurred with a significantly increased rate. In the male patients cancer of the skin occurred with a significantly reduced incidence, as did testicular cancer where the risk was 28% of that of the general population. Also cancer of the colon and rectum, prostate and lung occurred with a notably low rate. Cancer of the digestive tract and of the genital organs was reduced in the males but this reduction was not statistically significant. In the females no single group of cancer was significantly reduced, but cancer of the female genital organs only occurred with 56% of the rate of the general population (p = 0.057). There was a tendency towards risk reduction both for cancer of the uterine cervix and endometrial carcinoma, cancer of the ovary and melanoma of the skin. In the total material no males and one female
188
P.B. Mortensenlschizophrenia
Table 1 Standardized Tumour
cancer
incidence
site
rate ratios
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(SIR) in schizophrenic
Males
patients
1970-1987
Females
No. of cases
SIR
All sites’ Buccal cavity Digestive tract Respiratory system Lung Breast Male genital organs Testis
47 2 7 7 6 0 5 2
0.68 0.91 0.53 0.60 0.62 0.00 0.45 0.28
b N.S. p=O.lO N.S. N.S. N.S. pzo.07 ’
_
Female genital organs Urinary system Skin Melanoma of skin Uther specified sites Metastases Other and unspecified sites Lymphatic and haematopoietic system
~ 10 3 0 4 3
1.59 0.24 0.00 0.77 3.09
N.S. b p=o.o7 N.S. N.S.
11 5 13 1 2 3
1
1.92
N.S.
5
0.76
N.S.
N.S. p>O.lO. “Indicates individuals bp
in Denmark
Males + females
No. of cases
SIR
No. of cases
SIR
86 0 19 9 7 22
0.86 0.00 0.98 1.18 1.02 0.88
N.S. N.S. N.S. N.S. N.S. N.S. _
133 2 26 16 13 22 _
0.79 0.58 0.80 0.83 0.78 0.87
b N.S. N.S. N.S. N.S. N.S.
0.56 1.13 0.87 0.26 0.43 2.34
p=o.o51 N.S. N.S. N.S. N.S. N.S.
~ 15 16 1 6 6
1.40 0.59 0.14 0.61 2.67
N.S. c c N.S. p=o.o54
2
1.92
N.S.
3
1.92
N.S.
6
1.18
N.S.
11
0.94
N.S.
with at least one cancer.
had developed melanoma of the skin versus an expectation based on the population rates of 6.95. This risk reduction (IRR = 0.14) was statistically significant (p=O.Ol). As for cancer occurrence prior to the first schizophrenia admission, 68 schizophrenic patients, 31 males and 37 females, had a cancer diagnosis prior to their first schizophrenia admission. This was significantly less than the population based expected number (RR= 0.77 p =0.03). This reduced rate, however, was limited to the female patients (RR=0.60 p=O.O03) whereas the rates in males did not differ from the general population (RR= 1.07 p=O.46). No single group of tumors were found with a rate significantly different from general population rates, but a relatively low rate of female genital cancers (RR=0.60 p =O. 10) and skin cancer (RR=0.48 p =0.12) accounted for more than 50% of the reduced rate in females. In Table 2 the standardized incidence ratios for some selected types of cancer and for all types of
cancer are presented, adjusted for the smoking habits among first admitted psychiatric inpatients. The focus is here on cancers with known relation to tobacco smoking. Although the results of this adjustment should be interpreted with some caution, the findings reported in Table 2 demonstrated that the finding of a reduced cancer incidence in schizophrenic patients is even more marked when smoking habits are taken into account. The estimated adjusted SIR for males was 0.60 and for females 0.70. The effect of this adjustment is particularly marked in the female patients.
4. Discussion 4.1. Methodological problems Apart from the reduced rates of cancer of the testes, and of malignant melanoma in the total material, the findings regarding specific sites and
P. B. MortensenlSchizophrenia Table 2 Smoking
adjusted
SIR, for cancer
in schizophrenic
patients
selected sites Males + females
Females
All sites Lung Bladder Kidney Pancreas
189
Research 12 (1994) 185-194
No. of cases
Adjusted SIR
SIR
No. of cases
Adjusted SIR
SIR
No. of cases
Adjusted SIR
SIR
47 6 6 4 2
0.60 0.44 1.18 1.87 1.08
0.68 0.62 1.39 2.01 1.22
86 1 1 4 0
0.70 0.64 0.35 1.42 0.00
0.86 1.02 0.44 1.83 0.00
133 13 7 8 2
0.66 0.53 0.88 1.61 0.41
0.79 0.78 1.06 1.91 0.48
groups of sites were not statistically significant. This highlights the problems described e.g. by Baldwin, ( 1979) of achieving sufficient sample sizes in order to get reasonable statistical power, when studying the occurrence of one disorder as cancer, in a patient group with another disorder with relatively low incidence. Statistical power in the present study was further compromised by the low mean age, and thus low baseline risk for cancer, of the study population. This is illustrated by the fact that the total expected number of cancer cases was no more than approximately 168 in this study of 9156 patients representing a total of more than 70,000 person years of follow-up. However, the finding of a reduced incidence of cancer in schizophrenic males, and of an incidence of all cancers in female schizophrenics similar to that of the general population, replicates the finding in previous studies of a cohort of chronic schizophrenic inpatients (DuPont et al., 1986; Mortensen 1989). Possible explanations for this include methodological problems, altered exposure to known risk factors for cancer and hypotheses about the role of neuroleptics and other issues related to schizophrenia and psychiatric treatment. A number of studies, recently reviewed by Adler and Griffith, (1991), demonstrate the difficulties of diagnosing physical disorders in schizophrenic and other psychiatric patients. These diagnostic difficulties might have resulted in an artificial finding of a reduced cancer risk. However, if that were the case, one would expect that a higher proportion of cancer cases than in the general population had been identified on the basis of an unexpected finding of a tumor at autopsy. The autopsy rate
-
in the study population was 33.8% vs. the autopsy rate in the general population of 35% in the average year of death in the study population. After indirect standardization for age, however, the autopsy rate among the schizophrenic patients was 17.9% in suicides vs. the expected 16.5% (n.s.), and in all other causes of death it was 47.5% vs. expected 40.8% (~~0.01). Cancer is in general only rarely diagnosed as an unexpected finding at autopsy (Asrues, 1984), as was the case in a study of 108 schizophrenic cancer patients (Mortensen, 1987b), and the fact that cancer in the present study population only in 17 or 12.8% of the cases were reported to be diagnosed during the last month prior to death, together with the comparatively high autopsy rate makes it unlikely that the reduced cancer incidence is only an artifact caused by reduced diagnostic accuracy of cancer in schizophrenics. If there was an earlier onset of cancer in individuals who later develop schizophrenia, than in the general population, one might also hypothesize that the reduced incidence of cancer was an artifact caused by this selection, i.e., the more ‘cancer prone’ patients would already have developed cancer before the onset of schizophrenia and would thus not be included in cancer incidence studies in schizophrenics. If one accepts the assumption that the survival prior to schizophrenia in those who developed cancer does not differ from the survival of other cancer patients, this explanation for the reduced cancer incidence was refuted, however, by the finding in the present study population of first admitted schizophrenics, of a low rate of cancer prior to the first schizophrenia admission. The
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P.B. MortensenJSchizophrenia
reduced rates in females may seem contradictory to the findings regarding incidence, where the reduction was more marked in the males. However, even though there were fewer females than males in the study population, the higher age at schizophrenia onset in females made it more likely to detect any differences in cancer rates prior to schizophrenia onset in females than in males. The fact that cancer rates prior to schizophrenia were reduced, indicates that at least not all of the reduced incidence can be ascribed to factors relating to schizophrenia treatment, e.g., neuroleptics, even though this treatment admittedly may have started long before the first admission. It is an open question if this possible early reduction in cancer risk should be ascribed to constitutional, e.g. genetic factors, or differential exposure to environmental risk factors. 4.2. Exposure
to established
risk factors for cancer
Bearing in mind that most evidence in the present study regarding the incidence of specific tumors is not conclusive, it still is noteworthy that the direction of change in the incidence of most tumors was consistent with the findings of the previous Danish studies. The most striking finding regarding subtypes was probably that respiratory cancers tended to occur less frequently than in the general population. The risk reduction was not statistically significant, and was less marked than in a previous study of chronic schizophrenic patients (Mortensen, 1989), where the relative risk for lung cancer was 0.32 vs 0.78 in the present study. It is possible that this difference is an artifact arising because of the differing age distributions in the two study populations, making the indirectly standardized rates incomparable (Breslow and Day, 1987). When smoking habits are taken into account (Table 2), however, the relative risk in the present study was even more reduced, and it appears likely that prolonging the follow up with the resulting increase in statistical power would replicate previous findings of a reduced lung cancer risk in schizophrenic patients. In this context it should also be noted that the effect of the adjustment for smoking habits was
Research 12 (1994) 185-194
that the cancer risk reduction in females approached the level found in the male patients. This may suggest that there is no difference in cancer risk reduction in schizophrenics that can be ascribed specifically to gender. Rather gender differences could be interpreted as a result of confounding caused by the fact that the smoking habits of schizophrenic females differed more from those of the general population, than did the smoking habits of the male patients. Also the difference in relative cancer risk between males and females in the prior studies of chronic schizophrenic inpatients (DuPont et al., 1986; Mortensen, 1989) could be interpreted as a result of the fact that the relevant general population rates of lung cancer in females in that study period were low, so that the observed reduction in lung cancer risk did not have any substantial effect on the overall rates of cancer in females in that cohort. It must be concluded that there at present is no definite evidence of other gender specific differences of cancer rates in schizophrenia than those found in the general population. The marginally significant reduction in the risk for male and female genital cancers is in accordance with the previous study. In the study of chronic long stay patients it seemed reasonable to ascribe at least part of this reduced risk for especially cancer of the uterine cervix, and possibly prostate cancer, to reduced sexual activity (Rotkin, 1977; Zaridze and Boyle, 1987). It is an open question if the same assumption would be valid in the present day population of schizophrenic patients, as little empirical evidence exists regarding the sexual habits of this group of patients. Clinical impressions would probably range from that of a reduced sexual activity as an aspect of general social isolation, to that of an increased sexual activity associated with a relative promiscuity in a smaller group of these patients. If reduced sexual activity is contributing to the reduced cancer risk, this may also be relevant to the reduced rates of female genital cancers prior to the first schizophrenia admission. The risk reduction for skin cancers, including malignant melanoma, was even more marked than in the previous study. For all skin cancers the incidence rate ratio was 0.59 vs. 0.90 in the previ-
P.B. MortensenlSchi=ophreniu
ous study, and for malignant melanoma it was 0.14 vs. 1.14. Even though comparisons of indirectly standardized rates, as stated above, may be highly misleading, one might speculate that the findings reflect that schizophrenic patients have not experienced the same increase in skin cancer risk as the general Danish population. A possible hypothetical explanation could be that schizophrenics are less exposed to risk factors for these cancers, e.g. sunbathing (Rlsterlind, 1990), than other Danes in the same age groups. The reduced incidence of testicular cancer is difficult to explain in terms of altered exposure to environmental risk factors, as few such risk factors are known for testicular cancer (Senturia, 1987). Cryptorchidism is the main known risk factor, possibly together with genetic factors, and there is no evidence in the literature regarding the occurrence of cryptorchidism in males who later develop schizophrenia. In the absence of any studies of risk for testicular cancer, or any other cancer, in the relatives of schizophrenic patients, any hypothesis regarding a genetic antagonism between cancer and schizophrenia must remain speculative as long as the genetic mechanisms involved in the causation of either disease or group of diseases are unknown. As demonstrated in Table 2 differences in tobacco smoking habits between schizophrenic patients and the general population will not help in explaining the reduced cancer risk in these patients. The literature would suggest that schizophrenics are more exposed to alcohol than the general population (Craig and Kovasznay, 1988), and there are no reports of the dietary practices of schizophrenics to suggest this as an explanation for reduced cancer incidence. Schizophrenic patients are undoubtedly less exposed to potentially carcinogenic occupational environments than the general population, but as occupational exposures only are assumed to account for a very limited proportion of cancer risk (Doll and Peto, 1981) this is also an unlikely explanation for the reduced cancer risk in schizophrenia. 4.3. Neuroleptics
and cancer
It has been claimed that neuroleptic treatment was unlikely to explain a reduced cancer occur-
Research 12 (1994) 185-194
191
rence in schizophrenic patients as the first reports of this reduction were made long before the introduction of neuroleptics (Fox and Howell, 1974). However, in the same paper Fox and Howell demonstrate that these early reports are based on proportionate mortality studies, a methodology that will tend to underestimate cancer mortality in the presence of an increased mortality from other causes. As all papers that find a reduced cancer risk in schizophrenia prior to the introduction of neuroleptics are proportionate mortality studies (Btiel 1925; Hahnemann 1931), and as studies from the same period using more appropriate methodology find no such differences (Opsahl, 1933; Alstrom 1942; Odegaard 1951; Scheflen 1951), these data would not be incompatible with neuroleptics as an explanation for lowered cancer risk. Three different lines of evidence are suggestive of an antineoplastic effect of neuroleptics. First, a number of casuistic reports have been made of an unexpected regression of tumors when the patient for psychiatric reasons was treated with neuroleptics (Osterman, 1961; Ltihrs and Gertich, 1962; Csatary, 1972; Eicke, 1973; 1975; Hercbergs, 1988). In this context one could also mention reports of open (phase I/II) clinical trials (Miller et al., 1988; Hait et al., 1989) suggesting that some neuroleptics reverse resistance towards cytostatic treatment. A second line of evidence is a number of animal studies suggesting that chlorpromazine and other neuroleptics inhibit the growth of various experimentally induced or implanted tumors (for a review see Jones, 1985), and a recent report of enhancing radiation induced chlorpromazine damage in the bone marrow mice, suggesting a possible role for chlorpromazine as an adjunct in cancer treatment (Jagetia, 1992). Finally, a case control study comparing treatment histories of schizophrenics who did develop prostate cancer to the treatment of those who did not, have found neuroleptics to reduce the risk of developing this cancer (Mortensen, 1992). Another study reported a similar effect on cancer of the bladder, uterine cervix, and breast lung, (Mortensen, 1987a). However, a recent reanalysis of the data from that study (Mortensen, in prepa-
192
P. B. MortmsmlSchi,-ophrenia
ration) with an expansion of the control series and using a more appropriate statistical technique, did not replicate the significant association between neuroleptic treatment and reduced cancer risk, although the non-significant trend was still in the same direction, and although chlorpromazine had a marginally significant reducing effect on breast cancer risk. Early reports stating that reserpine treatment for hypertension increased breast cancer risk (Boston Collaborative Drug Surveillance Program, 1974; Armstrong et al., 1974; Heinonen et al., 1974) raised the concern that neuroleptics sharing the prolactine elevating effect of reserpine might induce breast cancer (Schyve et al., 1978). No studies found such an effect of neuroleptics (Overall, 1978), and a number of later studies have not confirmed the role of reserpine as a risk factor for breast cancer (Laska et al., 1975; Mack et al.; 1975; O’Fallon et al., 1975; Armstrong et al., 1976). However, in the case control study in schizophrenic patients mentioned above, as well as in the reanalysis (Mortensen, 1987a; Mortensen, in preparation) where reserpine had been used as an antipsychotic drug in much higher dosages than those used in the treatment of hypertension, reserpine significantly increased breast cancer risk when controlling for other neuroleptic treatment, so that study might suggest that the risk increasing effect of reserpine on breast cancer that was demonstrated is not mediated through the elevation of serum prolactine levels, as other neuroleptic treatment either had no effect or a reducing effect on breast cancer risk.
5. Conclusion A reduced cancer incidence in 9 156 first admitted schizophrenic patients most markedly in males, was found in the present study, hereby replicating a previous study of chronic schizophrenic inpatients. Methodological problems are unlikely to explain this finding. Apart from the possible contribution to reduced risk for female genital cancer by reduced sexual activity, this reduction of cancer risk is not readily
Research 12 (1994) 185-194
interpretable as an effect of reduced exposure to established risk factors for cancer, and the smoking habits of psychiatric patients would lead to the expectation of an increased rather than a reduced cancer risk. There is some evidence available in the literature consistent with the hypothesis of an antineoplastic effect of neuroleptics as an explanation for these findings. No increase of breast cancer risk was found, suggesting that neuroleptic treatment does not increase breast cancer risk.
6. Acknowledgements The study was supported by a grant from Sygekassernes Helse-fond (Hl l/280-88), and Danish Medical Research Council (grant no. 12-9871-1).
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193
Harris, A.E. (1988) Physical disease and schizophrenia. Schizophr. Bull. 14, 85-96. Heinonen, O.P., Shapiro, S., Tuominen, L. and Turunen, MI. (1974) Reserpine use in relation to breast cancer. Lancet 2, 675-677. Hercbergs, A. (1988) Thioridazine: A radiation enhancer in advanced cervical cancer? Lancet 2, 737. Jagetia, G.C., (1991) Effect of chlorpromazine hydrochloride on the formation of micronuclei in the bone marrow of mice exposed to gamma radiation. Hereditas 115, 195-199. Jones, G.R. (1985) Cancer therapy: phenothiazines in an unexpected role. Tumori 71, 563-569. Juul, S. (1984) Programmer til overlevelsesberegninger, rapp. nr. 1. Aarhus: Socialmedicinsk Institut, Aarhus Universitet. Laska, E.M., Siegel, C., Meisner, M., Fischer, S. and Wanderling, J. (1975) Matched-pairs study of reserpine use and breast cancer. Lancet 2, 2966300. Ltihrs, W. and Gertich, I. (1962) Uber die Kombinationsbehandlung mit entkoppelnden Substanzen bei malignen Tumoren. Krebsarzt 17, 4055410. Mack, T.M., Henderson, B.E., Gerkins, V.R., Arthur, M., Baptista, J. and Pike, M.C. (1975) Reserpine and breast cancer in a retirement community. N. Engl. J. Med. 292, 1366-1371. Masterson, E. and O’Shea, B. (1984) Smoking and malignancy in schizophrenia. Br. J. Psychiatry 145, 429-432. Miller, R.L., Bukowski, R.M., Budd, G.T., Purvis, J., Weick, J.K., Shepard, K., Midha, K.K. and Ganapathi, R. (1988) Clinical modulation of doxorubicin resistance by the calmodulin-inhibitor, trifluoperazine: a phase I/II trial. J. Clin. Oncol. 6, 880-888. Mortensen, P.B. (1987a) Neuroleptic treatment and other factors modifying cancer risk in schizophrenic patients. Acta Psychiatr. Stand. 75, 5855590. Mortensen, P.B. (1987b) Diagnosis of cancer and autopsy rate in schizophrenic patients. Ugeskr. Laeger 149, 197331975. Mortensen, P.B. (1989) The incidence of cancer in schizophrenic patients. J. Epidemiol. Community Health 43, 43-47. Mortensen, P.B. (1992) Neuroleptic medication and prostatic cancer risk in schizophrenic patients. Acta Psychiatr. Stand. 85, 390-393. Mortensen, P.B. and Juel, K. (1990) Mortality and causes of death in schizophrenic patients in Denmark. Acta Psychiatr. Stand. 81, 372-377. Munk-Jorgensen, P. and Mortensen, P.B. (1989) Schizophrenia: a 13-year follow-up. Acta Psychiatr. Stand. 79, 391-399. Munk-Jorgensen, P. (1987) Why has the incidence of schizophrenia in Danish psychiatric institutions decreased since 1970? Acta Psychiatr. Stand. 75, 62268. Nakane, Y. and Ohta, Y. (1986) The example of linkage with a cancer register. In: G.H.M.M. ten Horn, R. Giel, W. Gulbinat, J.H. Henderson (Eds.) Psychiatric Case Registers in Publich Health. A Worldwide Inventory 1960&1985. Elsevier, Amsterdam. pp. 240-245. Nielsen, P.E. Zacho, J., Olsen J.A. and Olsen, C.A. (1988)
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Aendringer i danskernes rygevaner 1970- 1987. Ugeskr. Laeger 150, 2229-2233. O’Fallon, W.M., Labarthe, D.R. and Kurland, L.T. (1975) Rauwolfia derivatives and breast cancer. Lancet 2, 2922296. Opsahl, R. (1933) Om krefthyppigheten blandt sinnssyke. Norsk Mag. Lzgevidenskaben 94, 771-790. Osterman, E. (1961) Har klorpromazin en cytostatisk verkan? Nordisk Psykiatrisk Tidsskr. 15, 154-159. Overall, J.E. (1978) Prior psychiatric treatment and the development of breast cancer. Arch. Gen. Psychiatry 35, 898-9. Rotkin, J.D. (1977) Studies on the epidemiology of cervix cancer: Expanded Sampling. Cancer Treatment Rep. 61, 1733180. Schyve, P.M., Smithline, F. and Meltzer, H.Y. (1978) Neuroleptic-induced prolactin level elevation and breast cancer: an emerging clinical issue. Arch. Gen. Psychiatry 35, 1291&1301.
Research I2 (1994) 185-I 94 Scheflen, A.E. (1951) Malignant tumors in the institutionalized psychotic population. Arch. Neural. Psychiatry 66, 1455155. Senturia, Y.D. (1987) The epidemiology of testicular cancer. Br. _I. Urol. 60, 2855291. Simpson, J.C. (1988) Mortality studies in schizophrenia. In: M.T. Tsuang and J.C. Simpson (Eds.) Handbook of Schizophrenia. Nosology, Epidemiology and Genetics of Schizophrenia. Elsevier, Amsterdam. pp. 245-274. Zaridse, D.G. and Boyle, P. (1987) Cancer of the prostate: Epidemiology and aetiology. Br. J. Ural. 59, 493-502. Zilber, N., Schufman, N. and Lerner, Y. (1989) Mortality among psychiatric patients-the groups at risk. Acta Psychiatr. Stand. 79, 248-256. Odegaard, 0. (1951) Mortality in Norwegian mental hospitals 1926-1941. Acta Genet. Statist. Med. 2, 141-173. (asterlind, A. (1990) Malignant melanoma in Denmark. Occurrence and risk factors. Acta Oncol. 29, 8333854.
Schizophrenia Research 12 (1994) 185-194
The occurrence of cancer in first admitted schizophrenic patients Preben Bo Mortensen* Institute of Basic Psychiatric Research, Department of Psychiatric Demography, Psychiatric Hospital in Aarhus, K-8240 Risskov, Denmark (Received
1 August
1992; revision received
1 September
1993; accepted
10 September
1993)
Abstract The incidence of cancer was studied in a cohort of all first admitted 9156 patients in Denmark with a diagnosis of schizophrenia in the period 1970-1987. The overall incidence of cancer was reduced particularly in the males. Adjustment for the smoking habits of psychiatric patients enhanced this risk reduction. Fewer than expected had been diagnosed with cancer prior to the first schizophrenia admission. This tendency was limited to the female patients. The reduced cancer incidence was particularly marked for genital cancers, in particular testicular cancer, and skin cancers including malignant melanoma. Breast cancer risk was not increased, thus not substantiating concerns that neuroleptics would increase breast cancer risk through the elevation of serum prolactin levels. Some available evidence in the literature supports the hypothesis of an antineoplastic effect of neuroleptics as an explanation for the low occurrence of cancer in schizophrenic patients. Further large sample studies including an extension of the followup of this cohort are needed to establish the reduced risk of cancer in schizophrenic patients as well as exploring the causes for this reduction. Key words: Cancer incidence;
Smoking
1. Introduction A reduced occurrence of cancer in schizophrenic patients has been reported in the literature throughout most of this century (for reviews see Du Pan and Mtiller, 1977; Baldwin, 1979; Simpson, 1988). A number of methodological problems, however, have hampered especially the early reports, and the issue of whether schizophrenics differ from the general population in terms of cancer risk remains controversial (Fox and Howell, 1974; Harris, 1988). A number of studies of mortality in schizophrenic patients report the cause specific mortality from cancer (e.g. Zilber et al., 1989; Mortensen *Corresponding 0920-9964/94/$7.00
author. 0 1994 Elsevier Science B.V. All rights reserved
SSDZ 0920-9964(94)E0071-2
and Juel, 1990; for a review see Simpson, 1988). However, cancer mortality does not only measure cancer incidence, but also the survival of those who develop cancer, and mortality from other causes may complicate the interpretation of cancer mortality data as indicators of cancer risk. It follows that cancer incidence rather than cancer mortality would be the preferable type of data when studying cancer risk in schizophrenia. A WHO multicenter study addressed this issue and the findings from the Danish study in this collaboration indicated a reduced incidence of some types of cancer (DuPont et al., 1986; Mortensen, 1989). The material in that study consisted of all schizophrenic patients in Danish psychiatric hospitals on a census day in 1957 (Arentsen and Striimgren, 1959), mainly chronic
186
P.B. Mortensen/Schizophrenia
patients with admissions to mental hospitals that often had lasted several decades. The Japanese study in the same WHO collaboration reported an increased breast cancer risk in young female patients (Nakane and Ohta, 1986), and in a study from Honolulu, Hawaii, in this collaboration female patients of Japanese origin had an increased cancer risk whereas male Japanese patients and Caucasian patients of both sexes did not differ significantly from the general population in terms of cancer risk (Gulbinat et al., 1992). An earlier incidence study reported no difference between schizophrenic patients and the general population (Ehrenteil, 1957). More limited sample size and other methodological issues in these studies, however, made it hard to arrive at firm conclusions. There were indications that tobacco smoking had been very limited in the cohort included in the previous Danish studies (DuPont et al., 1986; Mortensen, 1989) as opposed to what is the case in the present day population of schizophrenic in-patients (Masterson and O’Shea, 1984). However, only one previous study exists in the literature regarding the incidence of cancer in schizophrenic patients treated in the present day psychiatric hospital system (Baldwin, 1980), and in that study, reporting no difference of cancer incidence between schizophrenic patients and the general population, the sample size was not sufficiently large to allow any firm conclusions. The aim of the present study is to describe the incidence of cancer in a total national sample of first admitted schizophrenic patients in order to see whether the previous findings from old long stay patients with limited tobacco smoking can be replicated in the present day population of schizophrenic in-patients. Furthermore it will be attempted to evaluate if cancer occurrence is altered prior to the first schizophrenia admission in those who later develop schizophrenia.
2. Material and methods The material consisted of all 9156 persons, 5658 males and 3498 females, who were first admitted to a Danish psychiatric hospital or department
Research 12 (1994) 185-194
during the period April 1, 1970 to December 31, 1987, and who at least at one admission were diagnosed schizophrenia (ICD-8 295). The aim of the design was to include a sample representing the incident cases of schizophrenia, as opposed to prevalent cases. It was decided, however, not to base the inclusion in the study solely on the diagnosis from the first admission because only approximately half of those who eventually are diagnosed schizophrenia receive this diagnosis at their first psychiatric hospitalization (MunkJorgensen, 1987). The patients were all identified through The Danish Psychiatric Case Register. This nationwide register has been in operation on a computerized basis since 1969, covering all Danish psychiatric in-patient facilities since April 1, 1970 (DuPont, 1983). It was not within the scope of this study to examine the validity of the schizophrenia diagnosis in The Danish Psychiatric Case Register, but in a study of 53 schizophrenic patients from one catchment area selected along the same lines as in this study (Munk-Jorgensen and Mortensen, 1989), 45 of the 53 included patients met DSM-III criteria for schizophrenia, further three patient met these criteria except for the age of onset which was above 45, (and those fulfilled DSM-III-R criteria) and four could not be classified according to DSMIII because of lack of sufficient information in the case records (Munk-Jorgensen, unpublished data). There are no private psychiatric in-patient facilities in Denmark, and the present study population thus represents a total national sample of all first admitted psychiatric in-patients who are diagnosed schizophrenia. Cancer cases were identified through linkage with the nationwide Danish Cancer Registry, which has been in operation since 1947 (Clemmesen, 1965). The unique person identifier (CPR-number) was used as identification of the patient in The Cancer Registry. In this manner a total of 133 patients, 47 males and 86 females, who had developed cancer after their first admission to a psychiatric hospital with the diagnosis of schizophrenia, were identified. The total number and dates of deaths in the study population was known as of the 25.3.1988, through the routine linkage between The Danish Psychiatric Case Register and The Danish Central Person Registry.
P.B. MortensenlSchizophrenia
The relation between cancer risk in schizophrenics and the general Danish population was estimated by calculating the indirectly standardized incidence ratio i.e. by dividing the observed number of cancers with the corresponding expected number given the age-, gender-, and calendar period(1970-72, 1973-77, 1978-82, 1983-88) -specific number of person years in the study population and the corresponding general population cancer incidence rates made available by The Danish Cancer Registry. This calculation is analogous to the calculation of a standardized mortality ratio (SMR). All observations were calculated as starting on the first day of the first admission with a schizophrenia diagnosis and ending by the date of cancer diagnosis, the date of death or by censoring on the 25.3.1988. The calculations were made using the OLVP6 program developed by Juul, ( 1984). The two-tailed p-values are the exact p-values based on the Poisson distribution for the observed number of cancer cases multiplied by two. The cancer occurrence prior to the first schizophrenia admission was assessed by comparing the number of schizophrenic patients who were registered in the Danish Cancer Registry prior to the first day of the first schizophrenia admission, to the expected number of such cases standardized for age and gender. This expected number was calculated on the basis of the age and gender specific number of schizophrenic patients, and the age and gender specific proportion of the general population who had been registered in the Danish Cancer Registry, and who were alive on 1.1.1981 (Danish Cancer Registry 1985). Recent data show that tobacco smoking is more frequent among first admitted psychiatric inpatients than in the general Danish population. In a Danish sample of 163 first admitted psychiatric patients between 18-49 years old, 72.8% of males and 72% of females reported to be smokers (Mors and Sorensen, personal communication). The corresponding age specific figures for the general Danish population in 1987 are 49.6% and 41.5% in males and females respectively (Nielsen et al., 1988). The proportion of heavy smokers (> 15 cigarettes per day) was 53.1% and 43.9% in male and female psychiatric patients respectively. The proportion of heavy cigarettes smokers in the
187
Research I2 (1994) 185-194
general Danish population was 21.6% in males and 15.2% in females (Nielsen et al., 1988). In order to take this difference into account when calculation the expected number of smoking related cancers the relative risks for smokers versus non-smokers reported by Doll and Peto ( 1981) was used. The ‘adjusted’ expected number was calculated using the formula adjusted
expected
number
=
(ax RR+b) cxRR+d x expected
number
where a and b respectively denote the proportion of smokers and non-smokers among psychiatric first admitted patients and c and d respectively denote the corresponding proportions in the general population. RR is the relative risk between smokers and non-smokers for developing specific types of cancer as reported by Doll and Peto, (1981).
3. Results The incidence rate ratio for all cancers combined as well as main groups and selected subgroups of tumor sites are reported in Table 1. Male schizophrenic patients had a significantly reduced incidence of cancer, whereas the reduction in the females was not statistically significant. No type of cancer occurred with a significantly increased rate. In the male patients cancer of the skin occurred with a significantly reduced incidence, as did testicular cancer where the risk was 28% of that of the general population. Also cancer of the colon and rectum, prostate and lung occurred with a notably low rate. Cancer of the digestive tract and of the genital organs was reduced in the males but this reduction was not statistically significant. In the females no single group of cancer was significantly reduced, but cancer of the female genital organs only occurred with 56% of the rate of the general population (p = 0.057). There was a tendency towards risk reduction both for cancer of the uterine cervix and endometrial carcinoma, cancer of the ovary and melanoma of the skin. In the total material no males and one female
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P.B. Mortensenlschizophrenia
Table 1 Standardized Tumour
cancer
incidence
site
rate ratios
Research 12 (1994) 185-194
(SIR) in schizophrenic
Males
patients
1970-1987
Females
No. of cases
SIR
All sites’ Buccal cavity Digestive tract Respiratory system Lung Breast Male genital organs Testis
47 2 7 7 6 0 5 2
0.68 0.91 0.53 0.60 0.62 0.00 0.45 0.28
b N.S. p=O.lO N.S. N.S. N.S. pzo.07 ’
_
Female genital organs Urinary system Skin Melanoma of skin Uther specified sites Metastases Other and unspecified sites Lymphatic and haematopoietic system
~ 10 3 0 4 3
1.59 0.24 0.00 0.77 3.09
N.S. b p=o.o7 N.S. N.S.
11 5 13 1 2 3
1
1.92
N.S.
5
0.76
N.S.
N.S. p>O.lO. “Indicates individuals bp
in Denmark
Males + females
No. of cases
SIR
No. of cases
SIR
86 0 19 9 7 22
0.86 0.00 0.98 1.18 1.02 0.88
N.S. N.S. N.S. N.S. N.S. N.S. _
133 2 26 16 13 22 _
0.79 0.58 0.80 0.83 0.78 0.87
b N.S. N.S. N.S. N.S. N.S.
0.56 1.13 0.87 0.26 0.43 2.34
p=o.o51 N.S. N.S. N.S. N.S. N.S.
~ 15 16 1 6 6
1.40 0.59 0.14 0.61 2.67
N.S. c c N.S. p=o.o54
2
1.92
N.S.
3
1.92
N.S.
6
1.18
N.S.
11
0.94
N.S.
with at least one cancer.
had developed melanoma of the skin versus an expectation based on the population rates of 6.95. This risk reduction (IRR = 0.14) was statistically significant (p=O.Ol). As for cancer occurrence prior to the first schizophrenia admission, 68 schizophrenic patients, 31 males and 37 females, had a cancer diagnosis prior to their first schizophrenia admission. This was significantly less than the population based expected number (RR= 0.77 p =0.03). This reduced rate, however, was limited to the female patients (RR=0.60 p=O.O03) whereas the rates in males did not differ from the general population (RR= 1.07 p=O.46). No single group of tumors were found with a rate significantly different from general population rates, but a relatively low rate of female genital cancers (RR=0.60 p =O. 10) and skin cancer (RR=0.48 p =0.12) accounted for more than 50% of the reduced rate in females. In Table 2 the standardized incidence ratios for some selected types of cancer and for all types of
cancer are presented, adjusted for the smoking habits among first admitted psychiatric inpatients. The focus is here on cancers with known relation to tobacco smoking. Although the results of this adjustment should be interpreted with some caution, the findings reported in Table 2 demonstrated that the finding of a reduced cancer incidence in schizophrenic patients is even more marked when smoking habits are taken into account. The estimated adjusted SIR for males was 0.60 and for females 0.70. The effect of this adjustment is particularly marked in the female patients.
4. Discussion 4.1. Methodological problems Apart from the reduced rates of cancer of the testes, and of malignant melanoma in the total material, the findings regarding specific sites and
P. B. MortensenlSchizophrenia Table 2 Smoking
adjusted
SIR, for cancer
in schizophrenic
patients
selected sites Males + females
Females
All sites Lung Bladder Kidney Pancreas
189
Research 12 (1994) 185-194
No. of cases
Adjusted SIR
SIR
No. of cases
Adjusted SIR
SIR
No. of cases
Adjusted SIR
SIR
47 6 6 4 2
0.60 0.44 1.18 1.87 1.08
0.68 0.62 1.39 2.01 1.22
86 1 1 4 0
0.70 0.64 0.35 1.42 0.00
0.86 1.02 0.44 1.83 0.00
133 13 7 8 2
0.66 0.53 0.88 1.61 0.41
0.79 0.78 1.06 1.91 0.48
groups of sites were not statistically significant. This highlights the problems described e.g. by Baldwin, ( 1979) of achieving sufficient sample sizes in order to get reasonable statistical power, when studying the occurrence of one disorder as cancer, in a patient group with another disorder with relatively low incidence. Statistical power in the present study was further compromised by the low mean age, and thus low baseline risk for cancer, of the study population. This is illustrated by the fact that the total expected number of cancer cases was no more than approximately 168 in this study of 9156 patients representing a total of more than 70,000 person years of follow-up. However, the finding of a reduced incidence of cancer in schizophrenic males, and of an incidence of all cancers in female schizophrenics similar to that of the general population, replicates the finding in previous studies of a cohort of chronic schizophrenic inpatients (DuPont et al., 1986; Mortensen 1989). Possible explanations for this include methodological problems, altered exposure to known risk factors for cancer and hypotheses about the role of neuroleptics and other issues related to schizophrenia and psychiatric treatment. A number of studies, recently reviewed by Adler and Griffith, (1991), demonstrate the difficulties of diagnosing physical disorders in schizophrenic and other psychiatric patients. These diagnostic difficulties might have resulted in an artificial finding of a reduced cancer risk. However, if that were the case, one would expect that a higher proportion of cancer cases than in the general population had been identified on the basis of an unexpected finding of a tumor at autopsy. The autopsy rate
-
in the study population was 33.8% vs. the autopsy rate in the general population of 35% in the average year of death in the study population. After indirect standardization for age, however, the autopsy rate among the schizophrenic patients was 17.9% in suicides vs. the expected 16.5% (n.s.), and in all other causes of death it was 47.5% vs. expected 40.8% (~~0.01). Cancer is in general only rarely diagnosed as an unexpected finding at autopsy (Asrues, 1984), as was the case in a study of 108 schizophrenic cancer patients (Mortensen, 1987b), and the fact that cancer in the present study population only in 17 or 12.8% of the cases were reported to be diagnosed during the last month prior to death, together with the comparatively high autopsy rate makes it unlikely that the reduced cancer incidence is only an artifact caused by reduced diagnostic accuracy of cancer in schizophrenics. If there was an earlier onset of cancer in individuals who later develop schizophrenia, than in the general population, one might also hypothesize that the reduced incidence of cancer was an artifact caused by this selection, i.e., the more ‘cancer prone’ patients would already have developed cancer before the onset of schizophrenia and would thus not be included in cancer incidence studies in schizophrenics. If one accepts the assumption that the survival prior to schizophrenia in those who developed cancer does not differ from the survival of other cancer patients, this explanation for the reduced cancer incidence was refuted, however, by the finding in the present study population of first admitted schizophrenics, of a low rate of cancer prior to the first schizophrenia admission. The
190
P.B. MortensenJSchizophrenia
reduced rates in females may seem contradictory to the findings regarding incidence, where the reduction was more marked in the males. However, even though there were fewer females than males in the study population, the higher age at schizophrenia onset in females made it more likely to detect any differences in cancer rates prior to schizophrenia onset in females than in males. The fact that cancer rates prior to schizophrenia were reduced, indicates that at least not all of the reduced incidence can be ascribed to factors relating to schizophrenia treatment, e.g., neuroleptics, even though this treatment admittedly may have started long before the first admission. It is an open question if this possible early reduction in cancer risk should be ascribed to constitutional, e.g. genetic factors, or differential exposure to environmental risk factors. 4.2. Exposure
to established
risk factors for cancer
Bearing in mind that most evidence in the present study regarding the incidence of specific tumors is not conclusive, it still is noteworthy that the direction of change in the incidence of most tumors was consistent with the findings of the previous Danish studies. The most striking finding regarding subtypes was probably that respiratory cancers tended to occur less frequently than in the general population. The risk reduction was not statistically significant, and was less marked than in a previous study of chronic schizophrenic patients (Mortensen, 1989), where the relative risk for lung cancer was 0.32 vs 0.78 in the present study. It is possible that this difference is an artifact arising because of the differing age distributions in the two study populations, making the indirectly standardized rates incomparable (Breslow and Day, 1987). When smoking habits are taken into account (Table 2), however, the relative risk in the present study was even more reduced, and it appears likely that prolonging the follow up with the resulting increase in statistical power would replicate previous findings of a reduced lung cancer risk in schizophrenic patients. In this context it should also be noted that the effect of the adjustment for smoking habits was
Research 12 (1994) 185-194
that the cancer risk reduction in females approached the level found in the male patients. This may suggest that there is no difference in cancer risk reduction in schizophrenics that can be ascribed specifically to gender. Rather gender differences could be interpreted as a result of confounding caused by the fact that the smoking habits of schizophrenic females differed more from those of the general population, than did the smoking habits of the male patients. Also the difference in relative cancer risk between males and females in the prior studies of chronic schizophrenic inpatients (DuPont et al., 1986; Mortensen, 1989) could be interpreted as a result of the fact that the relevant general population rates of lung cancer in females in that study period were low, so that the observed reduction in lung cancer risk did not have any substantial effect on the overall rates of cancer in females in that cohort. It must be concluded that there at present is no definite evidence of other gender specific differences of cancer rates in schizophrenia than those found in the general population. The marginally significant reduction in the risk for male and female genital cancers is in accordance with the previous study. In the study of chronic long stay patients it seemed reasonable to ascribe at least part of this reduced risk for especially cancer of the uterine cervix, and possibly prostate cancer, to reduced sexual activity (Rotkin, 1977; Zaridze and Boyle, 1987). It is an open question if the same assumption would be valid in the present day population of schizophrenic patients, as little empirical evidence exists regarding the sexual habits of this group of patients. Clinical impressions would probably range from that of a reduced sexual activity as an aspect of general social isolation, to that of an increased sexual activity associated with a relative promiscuity in a smaller group of these patients. If reduced sexual activity is contributing to the reduced cancer risk, this may also be relevant to the reduced rates of female genital cancers prior to the first schizophrenia admission. The risk reduction for skin cancers, including malignant melanoma, was even more marked than in the previous study. For all skin cancers the incidence rate ratio was 0.59 vs. 0.90 in the previ-
P.B. MortensenlSchi=ophreniu
ous study, and for malignant melanoma it was 0.14 vs. 1.14. Even though comparisons of indirectly standardized rates, as stated above, may be highly misleading, one might speculate that the findings reflect that schizophrenic patients have not experienced the same increase in skin cancer risk as the general Danish population. A possible hypothetical explanation could be that schizophrenics are less exposed to risk factors for these cancers, e.g. sunbathing (Rlsterlind, 1990), than other Danes in the same age groups. The reduced incidence of testicular cancer is difficult to explain in terms of altered exposure to environmental risk factors, as few such risk factors are known for testicular cancer (Senturia, 1987). Cryptorchidism is the main known risk factor, possibly together with genetic factors, and there is no evidence in the literature regarding the occurrence of cryptorchidism in males who later develop schizophrenia. In the absence of any studies of risk for testicular cancer, or any other cancer, in the relatives of schizophrenic patients, any hypothesis regarding a genetic antagonism between cancer and schizophrenia must remain speculative as long as the genetic mechanisms involved in the causation of either disease or group of diseases are unknown. As demonstrated in Table 2 differences in tobacco smoking habits between schizophrenic patients and the general population will not help in explaining the reduced cancer risk in these patients. The literature would suggest that schizophrenics are more exposed to alcohol than the general population (Craig and Kovasznay, 1988), and there are no reports of the dietary practices of schizophrenics to suggest this as an explanation for reduced cancer incidence. Schizophrenic patients are undoubtedly less exposed to potentially carcinogenic occupational environments than the general population, but as occupational exposures only are assumed to account for a very limited proportion of cancer risk (Doll and Peto, 1981) this is also an unlikely explanation for the reduced cancer risk in schizophrenia. 4.3. Neuroleptics
and cancer
It has been claimed that neuroleptic treatment was unlikely to explain a reduced cancer occur-
Research 12 (1994) 185-194
191
rence in schizophrenic patients as the first reports of this reduction were made long before the introduction of neuroleptics (Fox and Howell, 1974). However, in the same paper Fox and Howell demonstrate that these early reports are based on proportionate mortality studies, a methodology that will tend to underestimate cancer mortality in the presence of an increased mortality from other causes. As all papers that find a reduced cancer risk in schizophrenia prior to the introduction of neuroleptics are proportionate mortality studies (Btiel 1925; Hahnemann 1931), and as studies from the same period using more appropriate methodology find no such differences (Opsahl, 1933; Alstrom 1942; Odegaard 1951; Scheflen 1951), these data would not be incompatible with neuroleptics as an explanation for lowered cancer risk. Three different lines of evidence are suggestive of an antineoplastic effect of neuroleptics. First, a number of casuistic reports have been made of an unexpected regression of tumors when the patient for psychiatric reasons was treated with neuroleptics (Osterman, 1961; Ltihrs and Gertich, 1962; Csatary, 1972; Eicke, 1973; 1975; Hercbergs, 1988). In this context one could also mention reports of open (phase I/II) clinical trials (Miller et al., 1988; Hait et al., 1989) suggesting that some neuroleptics reverse resistance towards cytostatic treatment. A second line of evidence is a number of animal studies suggesting that chlorpromazine and other neuroleptics inhibit the growth of various experimentally induced or implanted tumors (for a review see Jones, 1985), and a recent report of enhancing radiation induced chlorpromazine damage in the bone marrow mice, suggesting a possible role for chlorpromazine as an adjunct in cancer treatment (Jagetia, 1992). Finally, a case control study comparing treatment histories of schizophrenics who did develop prostate cancer to the treatment of those who did not, have found neuroleptics to reduce the risk of developing this cancer (Mortensen, 1992). Another study reported a similar effect on cancer of the bladder, uterine cervix, and breast lung, (Mortensen, 1987a). However, a recent reanalysis of the data from that study (Mortensen, in prepa-
192
P. B. MortmsmlSchi,-ophrenia
ration) with an expansion of the control series and using a more appropriate statistical technique, did not replicate the significant association between neuroleptic treatment and reduced cancer risk, although the non-significant trend was still in the same direction, and although chlorpromazine had a marginally significant reducing effect on breast cancer risk. Early reports stating that reserpine treatment for hypertension increased breast cancer risk (Boston Collaborative Drug Surveillance Program, 1974; Armstrong et al., 1974; Heinonen et al., 1974) raised the concern that neuroleptics sharing the prolactine elevating effect of reserpine might induce breast cancer (Schyve et al., 1978). No studies found such an effect of neuroleptics (Overall, 1978), and a number of later studies have not confirmed the role of reserpine as a risk factor for breast cancer (Laska et al., 1975; Mack et al.; 1975; O’Fallon et al., 1975; Armstrong et al., 1976). However, in the case control study in schizophrenic patients mentioned above, as well as in the reanalysis (Mortensen, 1987a; Mortensen, in preparation) where reserpine had been used as an antipsychotic drug in much higher dosages than those used in the treatment of hypertension, reserpine significantly increased breast cancer risk when controlling for other neuroleptic treatment, so that study might suggest that the risk increasing effect of reserpine on breast cancer that was demonstrated is not mediated through the elevation of serum prolactine levels, as other neuroleptic treatment either had no effect or a reducing effect on breast cancer risk.
5. Conclusion A reduced cancer incidence in 9 156 first admitted schizophrenic patients most markedly in males, was found in the present study, hereby replicating a previous study of chronic schizophrenic inpatients. Methodological problems are unlikely to explain this finding. Apart from the possible contribution to reduced risk for female genital cancer by reduced sexual activity, this reduction of cancer risk is not readily
Research 12 (1994) 185-194
interpretable as an effect of reduced exposure to established risk factors for cancer, and the smoking habits of psychiatric patients would lead to the expectation of an increased rather than a reduced cancer risk. There is some evidence available in the literature consistent with the hypothesis of an antineoplastic effect of neuroleptics as an explanation for these findings. No increase of breast cancer risk was found, suggesting that neuroleptic treatment does not increase breast cancer risk.
6. Acknowledgements The study was supported by a grant from Sygekassernes Helse-fond (Hl l/280-88), and Danish Medical Research Council (grant no. 12-9871-1).
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