Neuroleptic medication and reduced risk of prostate cancer in schizophrenic patients Mortensen PB. Neuroleptic medication and reduced risk of prostate cancer in schizophrenic patients. Acta Psychiatr Scand 1992: 85: 390-393.
1
A decreased incidence of cancer of the prostate has been demonstrated in a cohort of 6168 chronic schizophrenic patients followed up from 1957 to 1984. A case-control study was performed based on this cohort to determine the possible influence of neuroleptic treatment and other factors on the risk of developing prostate cancer. Thirty-eight male schizophrenic patients who had developed prostate cancer during the observation period were compared with 76 age- and sex-matched controls from the same cohort. The only significant association was that of a reduced risk of prostate cancer among those who had been treated with a cumulative dose of high-dose phenothiazines (primarily chlorpromazine) of 15 g or more. These patients had been treated with an average daily dose of 145 mg chlorpromazine for an average of 12.5 years. N o other significant risk factors were identified.
Although prostate cancer is one of the most frequent tumors in men, relatively little is known about the causes of this disease. Various hormonal factors have been implicated in the causation of prostate cancer. No clear pattern of hormonal aberrations has been found in patients with prostate carcinoma, but one of the more consistent results is an increased level of plasma prolactin, both compared with healthy controls and compared with patients with benign prostatic hyperplasia (1). High dietary fat intake has also been found to be related to prostate cancer risk (2). A decreased level of vitamin A intake has been associated with increased risk of prostate cancer in some studies (3-5), although one study has found the opposite relationship between vitamin A intake and prostate carcinoma (6). Decreased sexual activity as well as an increased sexual drive has been noted in prostate carcinoma patients. A history of venereal disease has also been found to increase cancer risk. Marital status is associated with risk of prostate cancer, with increasing risk in the following order: single, married, widowed and divorced (7, 8). Furthermore, sexually transmitted infections and occupational exposure to cadmium have been suggested as possible risk factors (1). The study of special population groups whose incidence of cancer differs from that of the general population and who have had special living conditions or lifestyles have traditionally been subject to
390
P. B. Mortensen Institute of Psychiatric Demography, Aarhus Psychiatric Hospital, Risskov, Denmark
Key words: schizophrenia; neuroleptic drug; cancer
P.B. Mortensen, Institute of Psychiatric Demography, Aarhus Psychiatric Hospital, DK-8240 Risskov, Denmark Accepted for publication November 30, 199 1
epidemiological cancer studies. This study is based on a cohort of schizophrenic patients with a decreased incidence of prostate carcinoma (9, 10) who have been subject to living conditions differing markedly from those of the general population. A possible risk-modifying effect of neuroleptic medication is of particular interest in this study population. Material and methods
A cohort consisting of all inpatients in Danish psychiatric hospitals on a census day in 1957 with a diagnosis of schizophrenia was followed through 1984 and reidentified in the Danish Cancer Registry. This was done to determine the incidence of cancer in this cohort of schizophrenic patients. The details of this study have previously been published (10). Using this method, 40 cases of prostate cancer were identified. The incidence of prostate cancer was lower (incidence rate ratio = 0.56, PtO.O1). The incidence rate ratio was rather homogeneous across the age groups, and did thus not indicate that the reduced overall rate was a result of diagnostic delay. The autopsy rate in the schizophrenic patients (47%) did not differ significantly from that of the general Danish population (43%). In a study of 108 cancer patients from this cohort, only 1 had received a cancer diagnosis as a result of the accidental finding of a tumour at autopsy, and it is thus concluded that the lowered incidence rate is not a result of a low-
Neuroleptics and prostate cancer ered detection rate of tumours in this cohort of schizophrenic patients (1 1). A case-control in-cohort study (12) was performed by selecting cases of prostate cancer together with 2 controls from the same cohort for each cancer patient. The controls were men matched within 5-year age groups to the cases selected using incidence-density sampling: controls were selected among all those who were at risk for developing prostate cancer at the time when the individual case received a cancer diagnosis (13). In this way the relative risk estimates resulting from the statistical analysis can be interpreted as incidence rate ratios (14). Information on such potential risk factors as marital status, duration of hospitalization, age at first psychiatric hospitalization and neuroleptic and other treatment was recorded from the individual case records of the patients. It was possible to get access to the case records of 38 of the 40 patients who developed prostate cancer and the final material thus consisted of 38 cases and 76 controls drawn from the same cohort of schizophrenic patients. Data analysis was performed using conditional logistic regression analysis (15).
Results The relationship between a number of exposures and cancer was initially tested for each variable separately: marital status, social group, occupation, age at first psychiatric admission, duration of psychiatric hospitalization, neuroleptic treatment in 18 groups, electroconvulsive therapy or similar treatment and lobotomy. When the data were reduced to the final model, the only exposures that were retained were either those that had significant or marginally significant association with cancer risk, or are well-known risk factors for prostate cancer. Furthermore, factors that would seem to be important confounders for the other risk factors in the final model were included. The final model is shown in Table 1. The only factor that was significantly associated with cancer incidence was exposure to a cumulative dose
Table 1.
Mental hospital inpatient > 30 years Single vs married, divorced or widowed Treatment with perphenazine and other moderate dose phenothiazines Treatment with chlorpromazine and other high dose phenothiazines (cumulate dose > 500 defined daily dosage) Ever treated with neuroleptics
* PC0.05 t
Incidence rate ratio
95% confidence limits
1.96 0.50
(0.55-7.02) (0.17-1.46)
2.44
(0.84-7.04)
0.33" 1.37
(0.12-0.94) .(0.41-4.56)
of high-dose phenothiazines (primarily chlorpromazine) of 15 g or more. In periods during which they were in treatment, they received an average daily dose of 145 mg of chlorpromazine and on average they had been treated for 12.5 years with this group of drugs. Patients who had received this cumulative dose of chlorpromazine had an incidence of prostate cancer approximately one third of the incidence among the patients who had never been treated with these drugs or had received less. Treatment with a moderate dosage of phenothiazines (primarily perphenazine) exhibited a nonsignificant tendency to increase cancer risk. The effects of these 2 groups of neuroleptics were separate from any general association between neuroleptic treatment and cancer, as the variable treatment with any neuroleptic medication did not have any effect. It was included in the final model, however, to control any association between cancer and the circumstances that led to neuroleptic treatment. As an example of such an association, one could hypothesize that patients with an unrecognized cancer causing pain or other physical complaints would be more disturbed and restless than patients without physical complaints, and would thus be more likely to receive treatment with neuroleptics. Marital status did not affect the incidence of prostate cancer significantly, although there was a trend towards single patients having approximately half the incidence of cancer of other patients (married, divorced or widowed). Finally, total admission time was included in the model to eliminate confounding from general effects of institutionalization, i.e., effect of diet, etc. This variable did not significantly affect cancer risk, although there was a tendency towards more cancer among those who had been admitted for 30 years or more.
Discussion The main finding of this study is the tendency towards lower cancer risk among those who had been treated with high-dose neuroleptics. As in any epidemiological study including many different risk factors, one might argue that this finding may be a result of multiple tests more than a real association between exposure to this treatment and the risk of developing prostatic carcinoma. The results from other epidemiological studies as well as other types of research, however, suggests that this is a real effect of chlorpromazine and related compounds and that this effect is relevant to other malignancies than prostate cancer. A similar effect of this group of drugs was found in 2 other case-control studies in the same cohort of schizophrenic patients for bladder cancer in men and breast cancer in female schizophrenics (1 1). Apart from the possibility of a pre-
39 1
Mortensen
ventive effect of phenothiazines on the development of prostate cancer, another possible effect could be inhibition of the growth of these tumours. In this way chlorpromazine might delay the occurrence of clinical signs and symptoms of cancer. A number of clinical observations have been reported (16- 19) of cancer patients who recovered when treated with chlorpromazine. Furthermore, an inhibitory effect of chlorpromazine and other phenothiazines on the growth of tumours in laboratory rodents has been found in a number of studies (20-26). The ability of very small amounts of chlorpromazine to interfere with oxidative metabolism in tumour mitochondria has been suggested as a possible mechanism of the antitumour action of phenothiazines (26). Also the phenothiazines thioridazine, trifluoperazine and chlorpromazine have been found to reverse multiple drug resistance in human cancer cells (27), and preliminary clinical studies suggest that trifluoperazine may enhance the response to chemotherapy in patients with cancer refractory to conventional treatment (28,29). When used in the management of cancer, phenothiazines and other neuroleptics are mainly used in treating nausea, vomiting and pain and symptoms of anxiety and psychoses (30). However, the findings of this study together with the preliminary evidence that has been cited above suggests that phenothiazines may contribute more directly to the treatment of cancer, but studies directly assessing the use of phenothiazines in cancer treatment are clearly needed. The finding of a risk-elevating effect of moderatedose phenothiazines, mainly perphenazine, was included even though this finding was not statistically significant, because of the hypothesis-generating and exploratory nature of this study. If this effect was real, a possible mechanism of action could be the prolactin-elevating effect of this medication, as high serum prolactin levels have been associated with an increased risk of developing prostate cancer (31). Although this effect is common to all neuroleptics, prolactin elevation is correlated positively with the clinical potency of neuroleptics, and perphenazine may well be the only one of the new, more potent neuroleptics that has been administered to this cohort of schizophrenic patients for a sufficiently long time to affect cancer risk. Neuroendocrine factors may also have influenced the generally low risk of prostate cancer in this cohort of schizophrenic patients. Although baseline prolactin levels are not significantly lowered in schizophrenic patients, basal levels of follicle-stimulating hormone and luteinizing hormone have been found to be reduced in chronic schizophrenic patients, and also testosterone has been reported to be reduced in male schizophrenic subjects (32). According to most studies, these hormonal aberrations would predict a
392
lowered incidence of prostate cancer among schizophrenic patients, although the role of gonadotropic hormones and testosterone in the causation and progression of prostate cancer is still unclear (31, 2). However, this speculation is purely hypothetical and further studies are needed to determine whether schizophrenic patients have an inherently reduced risk of prostate cancer because of hormonal abnormalities and to clarify whether perphenazine or any other neuroleptic increases the risk of developing prostate cancer or any other type of cancer. When interpreting the finding of a nonsignificant tendency towards more cancer among those who had been admitted to a psychiatric hospital for 30 years or more, one of the factors associated with institutionalization that must be considered is diet. A number of studies has suggested that an increased risk of prostate cancer is associated with diets high in animal fats, and high levels of vitamin A protect against prostate cancer (1, 2). A detailed description of the diet in Danish mental hospitals does exist (33). This suggests that, until 1960, vitamin A intake was lower than that of the general Danish population. The total dietary fat intake was not reported to be higher than in the general population, but the sources of this fat intake would comprise more dairy products, margarine, etc. and less meat and eggs than in the general population. The reduced vitamin A intake in schizophrenic patients could thus contribute to the nonsignificant effect of institutionalization, but as already mentioned, the effect of institutionalization was not statistically significant and is at best a proxy variable for dietary practices. Although marital status did not exhibit any separate significant effect in this study, the finding of a lowered risk among those who had never been married is in accord with the role of marital status in other studies (7, 8). Conclusion
Prostate cancer has comparatively few known environmental risk factors. A significant reduction of the incidence has been demonstrated in a population of chronic schizophrenic patients. This study demonstrated a significant association between reduced risk of prostate cancer and treatment with rather small doses of certain phenothiazines. Whether this could be the result of an inhibitory effect on carcinogenesis or on the growth of existing tumours cannot be concluded based on this study. Although phenothiazines do have a number of potentially serious side effects (34), they are remarkably nontoxic compared with conventional chemotherapeutic agents, so further clinical studies are indicated to clarify the potential usefulness of phenothiazines in cancer treatment.
Neuroleptics and prostate cancer Acknowledgements TI^^ author wishes to thank D~ J~~~ Overgaard, M,D,, D~ povl Munk-Jorgensen, M.D. and the staff of the Institute of Psychiatric Delnography for help and ,&ice during the of the study. This study was supported by Sygekassernes Helsefond (grant nr. H 11/25-87).
References 1. ZARIDZE DG, BOYLEP. Cancer of the prostate: epidemiology and aetiology. Br J Urol 1987: 59:493-502. 2. ROSEDP. The biochemical epidemiology of prostatic carcinoma. In: IP C. BIRTDF, ROGERSAE, METTLINC, ed. Dietary fat and cancer. New York: Alan R. Liss, 1986:4368. 3. ROTKIN JD. Studies on the epidemiology of prostatic cancer: expanded sampling. Cancer Treat Rep 1977: 61: 173-150. 4. SCHUMAN LM, MANDELJ, BLACKARDC, BAUERH, SCARKJ, MCHUGHR. Epidemiologic study of prostatic cancer: preliminary report. Cancer Treat Rep 1977:61: 181186. 5. HIRAYAMA T.Epidemiology of prostate cancer with special reference to the role of diet. Natl Cancer lnst Monogr 1979: 53: 149-155. 6. GRAHAMS. HAUGHEY B, MARSHALL J et al. Diet in the epidemiology of carcinoma of the prostate gland. J Natl Cancer Inst 1983: 70: 687-692. 7. KINGM, DIAMOND E, LILIENFELD AM. Some epidemiological aspects of cancer of the prostate. J Chronic Dis 1963: 16: 117-153. 8. LILIENFELD AM, LEVINML, KESSLER11. Cancer in the United States. American Public Health Association Monograph. Cambridge: Harvard University Press, 1972. 9. DUPONTA, JENSENOM, STROMGREN E, JABLENSKY A. Incidence of cancer in patients diagnosed as schizophrenic in Denmark. In: TEN HORN GHMM, GIEL R, GULBINAT JH, ed. Psychiatric case registers in pubWH, HENDERSON lic health. A worldwide inventory 1960-1985. Amsterdam: Elsevier, 1986:229-239. 10. MORTENSEN PB. The incidence of cancer in schizophrenic patients. J Epidemiol Community Health 1989:43:43-47. 1 1 . MORTENSEN PB. Neuroleptic treatment and other factors modifying cancer risk in schizophrenic patients. Acta Psychiatr Scand 1987:75:585-590. 12. PRENTICE RL. A case-cohort design for epidemiologic cohort studies and disease prevention trials. Biometrika 1986: 73: 1-11, 13. MORTENSEN PB. Ambidirectional studies - an extension of longitudinal studies in psychiatry. Psychiatr Dev 1988: 2: 173- 18 1. 14. FLANDERS WD, LOUVWC. The exposure odds ratio in nested case-control studies with competing risks. Am J Epidemiol 1986: 124: 684-692. 15. BRESLOW NE, DAY NE. Statistical methods in cancer research. The analysis of case-control studies. Lyon: IARC Scientific Publications, 1980 (No. 32). 16. LUHRSW. GERTICHI. Uber die Kombinationsbehandlung
mit entkoppelnden Substanzen bei malignen Tumoren. Krebsarzt 1962: 17: 405-410. 17. OYERMAN E. Har klorpromazin en cytostatisk verkan? Nordisk Psykiatr Tidsskr 1961: 15: 154-159. 18. CSATARY LK. Chlorpromazines and cancer. Lancet 1972:
12: 338-339. 19. EICKEW-J. Gunstige Verlaufe bei Karzinompatienten unter zusatzlicher Behandlung mit Phenothiazinderivaten. Med Klin 1975:70: 186-189. H, MICHELI. Effect of 20. HILF R, BELLC, GOLDENBERG fluphenazine H C 1 on R3230AC mammary carcinoma and inammaryglandsoftherat. Cancer Res 197i:31: 1111-1117. F, KURETANI K. Antitumor activity of 21. HOSHIA, KANZAWA psychotropic drugs and their synergic action with cyclophosphamide. Chem Pharmacol Bull 1969: 17: 848-850. F, HOSHIA, KURETANIK. Relationship be22. KANZAWA tween antitumor activity and chemical structure in psychotropic agents. Gann 1970:61:529-534. K. Antitumor activity of 23. KANZAWAF,HOSHIA, KURETANI haloacetylphenothiazines against ascites sarcoma- 180.Gann
1972:63:225-229. AM, WATTENBERG LW. PRICEJM, BRYAN 24. PAMUKCU GT. Phenothiazine inhibition of intestinal and urinary bladder tumors induced in rats by braken fern. J Natl Cancer Inst
1971:47: 155-159. JS, MELNICK NK, QUINN FR et al. Psychotropic 25. DRISCOLL drugs as potential antitumor agents: a selective screening study. Cancer Treat Rep 1978:62:45-74. 26. JONESGRN. Cancer therapy: phenothiazines in an unexpected role. Tumori 1985: 71: 563-569.
S, SHIRAISHI N, KURATOMI Y, NAKAGAWA M, 27. AKIYAMA KUWANOM. Circumvention of multiple-drug resistance in human cancer cells by thioridazine, trifluoperazine, and chlorpromazine. J Natl Cancer Inst 1986: 76: 839-844. RM, BUDD GT et al. Clinical 28. MILLERRL, BUKOWSKI modulation of doxorubicin resistance by the calmodulininhibitor, trifluoperazine: a phase 1/11 trial. J Clin Oncol 1988:
6: 880-888. 29. HAITWN,MORRISS, LAZOJS et al. Phase I trial of combined therapy with bleomyzin and the calmodulin antagonist, trifluoperazine. Cancer Chemother Pharmacol 1989:23:358-
362. 30. PETERSONLG, LEIPMANM, BONGARB. Psychotropic medications in patients with cancer. Gen Hosp Psychiatry
1987: 9: 313-323. 31. GRIFFITHS K, DAVIESP, EATONCL et al. Cancer of the prostate: endocrine factors. Oxf Rev Reprod Biol 1987: 9: 192-259. 32. POWCHIK P, DAVISBM, DAVISKL. The neuroendocrinology of schizophrenia. In: HENNFA, DELISILE, ed. Handbook of schizophrenia, Vol 2, Neurochemistry and neuropharmacology of schizophrenia. Amsterdam: Elsevier, 1987: 337-376. 33. UHLE.Kostundersngelser i institutioner. Copenhagen: Sundhedsstyrelsen, IV/17,1967: 241-256. 34. BALDESSARINI RJ. Drugs and the treatment of psychiatric disorders. In: GILMANAG, GOODMANLS, RALL TW, MURADF, ed. The pharmacological basis of therapeutics. 7th edn. New York: Macmillan, 1985: 387-446.
393
1
A decreased incidence of cancer of the prostate has been demonstrated in a cohort of 6168 chronic schizophrenic patients followed up from 1957 to 1984. A case-control study was performed based on this cohort to determine the possible influence of neuroleptic treatment and other factors on the risk of developing prostate cancer. Thirty-eight male schizophrenic patients who had developed prostate cancer during the observation period were compared with 76 age- and sex-matched controls from the same cohort. The only significant association was that of a reduced risk of prostate cancer among those who had been treated with a cumulative dose of high-dose phenothiazines (primarily chlorpromazine) of 15 g or more. These patients had been treated with an average daily dose of 145 mg chlorpromazine for an average of 12.5 years. N o other significant risk factors were identified.
Although prostate cancer is one of the most frequent tumors in men, relatively little is known about the causes of this disease. Various hormonal factors have been implicated in the causation of prostate cancer. No clear pattern of hormonal aberrations has been found in patients with prostate carcinoma, but one of the more consistent results is an increased level of plasma prolactin, both compared with healthy controls and compared with patients with benign prostatic hyperplasia (1). High dietary fat intake has also been found to be related to prostate cancer risk (2). A decreased level of vitamin A intake has been associated with increased risk of prostate cancer in some studies (3-5), although one study has found the opposite relationship between vitamin A intake and prostate carcinoma (6). Decreased sexual activity as well as an increased sexual drive has been noted in prostate carcinoma patients. A history of venereal disease has also been found to increase cancer risk. Marital status is associated with risk of prostate cancer, with increasing risk in the following order: single, married, widowed and divorced (7, 8). Furthermore, sexually transmitted infections and occupational exposure to cadmium have been suggested as possible risk factors (1). The study of special population groups whose incidence of cancer differs from that of the general population and who have had special living conditions or lifestyles have traditionally been subject to
390
P. B. Mortensen Institute of Psychiatric Demography, Aarhus Psychiatric Hospital, Risskov, Denmark
Key words: schizophrenia; neuroleptic drug; cancer
P.B. Mortensen, Institute of Psychiatric Demography, Aarhus Psychiatric Hospital, DK-8240 Risskov, Denmark Accepted for publication November 30, 199 1
epidemiological cancer studies. This study is based on a cohort of schizophrenic patients with a decreased incidence of prostate carcinoma (9, 10) who have been subject to living conditions differing markedly from those of the general population. A possible risk-modifying effect of neuroleptic medication is of particular interest in this study population. Material and methods
A cohort consisting of all inpatients in Danish psychiatric hospitals on a census day in 1957 with a diagnosis of schizophrenia was followed through 1984 and reidentified in the Danish Cancer Registry. This was done to determine the incidence of cancer in this cohort of schizophrenic patients. The details of this study have previously been published (10). Using this method, 40 cases of prostate cancer were identified. The incidence of prostate cancer was lower (incidence rate ratio = 0.56, PtO.O1). The incidence rate ratio was rather homogeneous across the age groups, and did thus not indicate that the reduced overall rate was a result of diagnostic delay. The autopsy rate in the schizophrenic patients (47%) did not differ significantly from that of the general Danish population (43%). In a study of 108 cancer patients from this cohort, only 1 had received a cancer diagnosis as a result of the accidental finding of a tumour at autopsy, and it is thus concluded that the lowered incidence rate is not a result of a low-
Neuroleptics and prostate cancer ered detection rate of tumours in this cohort of schizophrenic patients (1 1). A case-control in-cohort study (12) was performed by selecting cases of prostate cancer together with 2 controls from the same cohort for each cancer patient. The controls were men matched within 5-year age groups to the cases selected using incidence-density sampling: controls were selected among all those who were at risk for developing prostate cancer at the time when the individual case received a cancer diagnosis (13). In this way the relative risk estimates resulting from the statistical analysis can be interpreted as incidence rate ratios (14). Information on such potential risk factors as marital status, duration of hospitalization, age at first psychiatric hospitalization and neuroleptic and other treatment was recorded from the individual case records of the patients. It was possible to get access to the case records of 38 of the 40 patients who developed prostate cancer and the final material thus consisted of 38 cases and 76 controls drawn from the same cohort of schizophrenic patients. Data analysis was performed using conditional logistic regression analysis (15).
Results The relationship between a number of exposures and cancer was initially tested for each variable separately: marital status, social group, occupation, age at first psychiatric admission, duration of psychiatric hospitalization, neuroleptic treatment in 18 groups, electroconvulsive therapy or similar treatment and lobotomy. When the data were reduced to the final model, the only exposures that were retained were either those that had significant or marginally significant association with cancer risk, or are well-known risk factors for prostate cancer. Furthermore, factors that would seem to be important confounders for the other risk factors in the final model were included. The final model is shown in Table 1. The only factor that was significantly associated with cancer incidence was exposure to a cumulative dose
Table 1.
Mental hospital inpatient > 30 years Single vs married, divorced or widowed Treatment with perphenazine and other moderate dose phenothiazines Treatment with chlorpromazine and other high dose phenothiazines (cumulate dose > 500 defined daily dosage) Ever treated with neuroleptics
* PC0.05 t
Incidence rate ratio
95% confidence limits
1.96 0.50
(0.55-7.02) (0.17-1.46)
2.44
(0.84-7.04)
0.33" 1.37
(0.12-0.94) .(0.41-4.56)
of high-dose phenothiazines (primarily chlorpromazine) of 15 g or more. In periods during which they were in treatment, they received an average daily dose of 145 mg of chlorpromazine and on average they had been treated for 12.5 years with this group of drugs. Patients who had received this cumulative dose of chlorpromazine had an incidence of prostate cancer approximately one third of the incidence among the patients who had never been treated with these drugs or had received less. Treatment with a moderate dosage of phenothiazines (primarily perphenazine) exhibited a nonsignificant tendency to increase cancer risk. The effects of these 2 groups of neuroleptics were separate from any general association between neuroleptic treatment and cancer, as the variable treatment with any neuroleptic medication did not have any effect. It was included in the final model, however, to control any association between cancer and the circumstances that led to neuroleptic treatment. As an example of such an association, one could hypothesize that patients with an unrecognized cancer causing pain or other physical complaints would be more disturbed and restless than patients without physical complaints, and would thus be more likely to receive treatment with neuroleptics. Marital status did not affect the incidence of prostate cancer significantly, although there was a trend towards single patients having approximately half the incidence of cancer of other patients (married, divorced or widowed). Finally, total admission time was included in the model to eliminate confounding from general effects of institutionalization, i.e., effect of diet, etc. This variable did not significantly affect cancer risk, although there was a tendency towards more cancer among those who had been admitted for 30 years or more.
Discussion The main finding of this study is the tendency towards lower cancer risk among those who had been treated with high-dose neuroleptics. As in any epidemiological study including many different risk factors, one might argue that this finding may be a result of multiple tests more than a real association between exposure to this treatment and the risk of developing prostatic carcinoma. The results from other epidemiological studies as well as other types of research, however, suggests that this is a real effect of chlorpromazine and related compounds and that this effect is relevant to other malignancies than prostate cancer. A similar effect of this group of drugs was found in 2 other case-control studies in the same cohort of schizophrenic patients for bladder cancer in men and breast cancer in female schizophrenics (1 1). Apart from the possibility of a pre-
39 1
Mortensen
ventive effect of phenothiazines on the development of prostate cancer, another possible effect could be inhibition of the growth of these tumours. In this way chlorpromazine might delay the occurrence of clinical signs and symptoms of cancer. A number of clinical observations have been reported (16- 19) of cancer patients who recovered when treated with chlorpromazine. Furthermore, an inhibitory effect of chlorpromazine and other phenothiazines on the growth of tumours in laboratory rodents has been found in a number of studies (20-26). The ability of very small amounts of chlorpromazine to interfere with oxidative metabolism in tumour mitochondria has been suggested as a possible mechanism of the antitumour action of phenothiazines (26). Also the phenothiazines thioridazine, trifluoperazine and chlorpromazine have been found to reverse multiple drug resistance in human cancer cells (27), and preliminary clinical studies suggest that trifluoperazine may enhance the response to chemotherapy in patients with cancer refractory to conventional treatment (28,29). When used in the management of cancer, phenothiazines and other neuroleptics are mainly used in treating nausea, vomiting and pain and symptoms of anxiety and psychoses (30). However, the findings of this study together with the preliminary evidence that has been cited above suggests that phenothiazines may contribute more directly to the treatment of cancer, but studies directly assessing the use of phenothiazines in cancer treatment are clearly needed. The finding of a risk-elevating effect of moderatedose phenothiazines, mainly perphenazine, was included even though this finding was not statistically significant, because of the hypothesis-generating and exploratory nature of this study. If this effect was real, a possible mechanism of action could be the prolactin-elevating effect of this medication, as high serum prolactin levels have been associated with an increased risk of developing prostate cancer (31). Although this effect is common to all neuroleptics, prolactin elevation is correlated positively with the clinical potency of neuroleptics, and perphenazine may well be the only one of the new, more potent neuroleptics that has been administered to this cohort of schizophrenic patients for a sufficiently long time to affect cancer risk. Neuroendocrine factors may also have influenced the generally low risk of prostate cancer in this cohort of schizophrenic patients. Although baseline prolactin levels are not significantly lowered in schizophrenic patients, basal levels of follicle-stimulating hormone and luteinizing hormone have been found to be reduced in chronic schizophrenic patients, and also testosterone has been reported to be reduced in male schizophrenic subjects (32). According to most studies, these hormonal aberrations would predict a
392
lowered incidence of prostate cancer among schizophrenic patients, although the role of gonadotropic hormones and testosterone in the causation and progression of prostate cancer is still unclear (31, 2). However, this speculation is purely hypothetical and further studies are needed to determine whether schizophrenic patients have an inherently reduced risk of prostate cancer because of hormonal abnormalities and to clarify whether perphenazine or any other neuroleptic increases the risk of developing prostate cancer or any other type of cancer. When interpreting the finding of a nonsignificant tendency towards more cancer among those who had been admitted to a psychiatric hospital for 30 years or more, one of the factors associated with institutionalization that must be considered is diet. A number of studies has suggested that an increased risk of prostate cancer is associated with diets high in animal fats, and high levels of vitamin A protect against prostate cancer (1, 2). A detailed description of the diet in Danish mental hospitals does exist (33). This suggests that, until 1960, vitamin A intake was lower than that of the general Danish population. The total dietary fat intake was not reported to be higher than in the general population, but the sources of this fat intake would comprise more dairy products, margarine, etc. and less meat and eggs than in the general population. The reduced vitamin A intake in schizophrenic patients could thus contribute to the nonsignificant effect of institutionalization, but as already mentioned, the effect of institutionalization was not statistically significant and is at best a proxy variable for dietary practices. Although marital status did not exhibit any separate significant effect in this study, the finding of a lowered risk among those who had never been married is in accord with the role of marital status in other studies (7, 8). Conclusion
Prostate cancer has comparatively few known environmental risk factors. A significant reduction of the incidence has been demonstrated in a population of chronic schizophrenic patients. This study demonstrated a significant association between reduced risk of prostate cancer and treatment with rather small doses of certain phenothiazines. Whether this could be the result of an inhibitory effect on carcinogenesis or on the growth of existing tumours cannot be concluded based on this study. Although phenothiazines do have a number of potentially serious side effects (34), they are remarkably nontoxic compared with conventional chemotherapeutic agents, so further clinical studies are indicated to clarify the potential usefulness of phenothiazines in cancer treatment.
Neuroleptics and prostate cancer Acknowledgements TI^^ author wishes to thank D~ J~~~ Overgaard, M,D,, D~ povl Munk-Jorgensen, M.D. and the staff of the Institute of Psychiatric Delnography for help and ,&ice during the of the study. This study was supported by Sygekassernes Helsefond (grant nr. H 11/25-87).
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