American Journal of Epidemiology Copyright © 1992 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved
Vol. 136, No. 11 Printed in U.S.A.
LETTERS TO THE EDITOR
RE: DEPRESSION, ANTIDEPRESSANT MEDICATION, AND CANCER Several large epidemiologic studies of human subjects have assessed, with conflicting results, a possible connection between depression and cancer incidence, mortality, or outcome. For example, the Western Electric Study continues to show a positive correlation between depressed personality and cancer incidence and mortality after 20 years of follow-up (1), while the Alameda County Study (2) and National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study (3), among others (4-6), have demonstrated no significant association. In contrast, Linkins and Comstock (7) reported a significantly higher rate of development of lung and other cancers in heavy smokers with premorbid depressed mood; Covey et al. (8) suggest that this finding might be attributable, at least in part, to the fact that depressed persons are less likely to quit smoking over time than nondepressed persons. Interestingly, although some of these studies have also assessed the possible contribution of other variables, such as age, alcohol intake, occupation, family history of cancer, body mass, and serum cholesterol (1,2), none have examined the use of antidepressant drugs as a risk factor for cancer development or outcome. Recently, we demonstrated that at doses equivalent to those used in the treatment of human depression, amitriptyline and fluoxetine accelerate the growth rate of cancer in tumor-bearing mice, as well as the development and growth rate of mammary cancer in dimethylbenzanthracene-treated rats (9). We have suggested that these drugs, and structurally similar agents (10), act as copromoters of tumor growth, rather than as true promoters or initiators, by binding to novel intracellular histamine receptors (H|C) present in cell microsomes and nuclei (9, 11, 12) as well as in brain membranes (13). In addition to their stimulation of tumor cell growth, amitriptyline and fluoxetine depress normal lymphocyte mitogenesis (9), suggesting that immune suppression might also contribute to their observed acceleration of tumor growth in vivo. While any relevance to humans remains to be proven, the findings in rodents suggest the possibility that patients with cancer could be adversely affected by the administration of tricyclic antidepressants or fluoxetine, as could subjects with a concomitant heavy exposure to known carcinogens, such as cigarette smoke. We hope that our findings stimulate epidemiologists to examine the
possibility that the drugs used to treat depression, rather than the depression itself, may, in certain circumstances, influence the course or development of human cancer.
1414
REFERENCES
1. Persky VW, Kempthorne-Rawson J, Shekelle RB. Personality and risk of cancer: 20-year follow-up of the Western Electric Study. Psychosom Med 1987; 49:435-49. 2. Kaplan GA, Reynolds P. Depression and cancer mortality and morbidity: prospective evidence from the Alameda County Study. J Behav Med 1988;11:1-13. 3. Zonderman AB, Costa PT, McCrae RR. Depression as a risk for cancer morbidity and mortality in a nationally representative sample. JAMA 1989; 262:1191-5. 4. Hahn RC, Petitti DB. Minnesota Multiphasic Personality Inventory-rated depression and the incidence of breast cancer. Cancer 1988;61:845-8. 5. Weissman MM, Nyers JK, Thompson WD, et al. Depressive symptoms as a risk factor for mortality and for major depression. In: Erlenmeyer-KJmling L, Miller NE, eds. Life-span research on the prediction of psychopathology. Hillsdale. NJ: Lawrence Erlbaum Assoc, Inc. 1986:251-60. 6. Dattore PJ, Shontz FC, Coyne L. Premorbid personality differentiation of cancer and noncancer groups: a test of the hypothesis of cancer proneness. J Consult Clin Psychol 1980:48:388-94. 7. Linkins RW, Comstock GW. Depressed mood and development of cancer. Am J Epidemiol 1990; 132:962-72. 8. Covey LS, Glassman A, Dalack GW. Re: "Depressed mood and development of cancer." (Letter). Am J Epidemiol 1991 ;134:324-5. 9. Brandes LJ, Arron RJ, Bogdanovic RP. et al. Stimulation of malignant growth in rodents by antidepressant drugs at clinically-relevant doses. Cancer Res 1992;52:3796-800. 10. Brandes LJ, Beecroft WA, Hogg GR. Stimulation of in vivo tumor growth and phorbol-ester induced inflammation by N,N-diethyl-2-4-(phenylmethyl)phenoxy-ethanamine HCI, a potent ligand for intracellular histamine receptors. Biochem Biophys Res Commun 1991; 179:1297-1304. 11. Brandes LJ, Bogdanovic RP, Tong J, et al. Intracellular histamine and liver regeneration: high affinity binding of histamine to chromatin, low affinity binding to matrix, and depletion of a nuclear storage pool following partial hepatectomy. Biochem Biophys Res Commun 1992; 184:840-7. 12. Brandes LJ, LaBella FS, Warrington RC. Increased therapeutic index of antineoplastic drugs in combination with intracellular histamine antagonists. J Natl Cancer Inst 1991 ;83:1329-36. 13. Brandes LJ, Bogdanovic RP, Cawker MD, et al.
Letters to the Editor Histamine and growth: interaction of antiestrogen binding site ligands with a novel histamine site that may be associated with calcium channels. Cancer Res 1987;47:4025-3l.
Lome J. Brandes Departments of Medicine and Pharmacology Manitoba Institute of Cell Biology Winnipeg, Manitoba R3E 0V9 Canada AN EDITOR COMMENTS The interesting suggestion by Brandes (I) that antidepressant medication predisposes to cancer in humans adds a new dimension to the debate as to whether depression increases the incidence of cancer. In our long-term follow-up study supported by the National Cancer Institute (grant R35-CA-49761) to screen for Pharmaceuticals that may be carcinogenic (2-4), we have accumulated cancer incidence data of up to 19 years of follow-up of 1,957 patients who filled at least one prescription for amitriptyline, one of the drugs tested in animals by Brandes et al. (5), and of 308 who received imipramine, another heterocyclic antidepressant drug. These drugs were dispensed at the Kaiser Permanente outpatient pharmacy in San Francisco, California, between July 1969 and August 1973, and all patients who obtained prescriptions there during that 4-year period have been followed up for cancer occurrence using the hospital records of the Kaiser Permanente Medical Care Program and the local Surveillance, Epidemiology, and End Results (SEER) program, supplemented by manual review of medical records (4). Expected numbers of cancer cases among users of a particular drug were calculated by applying the age- and sexspecific incidence rates observed in the entire cohort of 143,574 pharmacy users. Observed and expected cases of cancer at each site and all sites combined have been tabulated with follow-up from first prescription dispensing through 1976 initially for amitriptyline, through 1978 for imipramine, and every second year thereafter through 1988 for both drugs. Among the amitriptyline users, 195 developed cancer by the end of 1988. This was not significantly greater than the 182.7 cases expected (standardized morbidity ratio (SMR) = 1.07, 95 percent confidence interval (CI) 0.92-1.23). The standardized morbidity ratio for liver cancer was significantly elevated only in the analysis through 1984, with four cases observed and 1.05 expected, the lower 95 percent confidence limit of the observed cases being 1.09. By 1988, there were still four observed cases, but the expected number had risen to 1.75. In our setting of screening multiple drugs and multiple cancer sites many times, this
1415
single positive finding in 1984 could well be due to chance. The only other significant finding for this drug was a deficit of cases of pancreatic cancer, observed in the two analyses with followup through 1986 and 1988. In both of these, there were zero observed cases, with an upper 95 percent confidence limit of 3.69, the expected numbers being 4.45 and 5.09, respectively. Imipramine users have never shown a significant departure from their expected numbers of new cancer cases at any site. Through 1988, a total of 12 cases of cancer were observed and 15.6 were expected (SMR = 0.77,95 percent CI 0.40-1.34). Thus, these follow-up data do not appear to support a link between human cancer and these two antidepressant drugs used in an ordinary clinical setting, with the caveats that the dosage of the drug or our statistical power may not have been sufficient to detect a small effect. Our follow-up duration should have been more than adequate to detect the co-promoter effect proposed by Brandes. This database may also be used to explore the larger question of whether depression is linked to the subsequent development of cancer. In 19671973, 4,215 patients in this pharmacy cohort received a computer-stored diagnosis of depression from a physician in one of the outpatient clinics in the Kaiser Permanente San Francisco facility (psychiatry clinic not included), of which 3,893, or 92.4 percent, were in the department of medicine. Using the same analytic methodology, we looked at their occurrence of cancer through 1988. For all sites combined, there were 407 cases observed and 432.6 expected (SMR = 0.94, 95 percent CI 0.85-1.04). The only statistically significant departure from expectation was a deficit of breast cancer cases—75 observed and 95.7 expected (SMR = 0.78,95 percent CI 0.62-0.98). Thus, depression itself was not associated with subsequent cancer occurrence in this large cohort. This supports our previous negative findings for self-assessed depression (6). REFERENCES
1. Brandes LJ. Re: Depression, antidepressant medication, and cancer. (Letter). Am J Epidemiol 1992; 136:1414-15. 2. Friedman GD, Ury HK. Initial screening for carcinogenicity of commonly used drugs. J Natl Cancer Inst 198O;65:723-33. 3. Friedman GD, Ury HK. Screening for possible drug carcinogenicity: second report of findings. J Natl Cancer Inst 1983;71:1165-75. 4. Selby JV, Friedman GD, Fireman BH. Screening prescription drugs for possible carcinogenicity: eleven to fifteen years of follow-up. Cancer Res 1989;49:5736-47. 5. Brandes LJ, Arron RJ, Bogdanovic RP, et al. Stimulation of malignant growth in rodents by antidepressant drugs at clinically relevant doses. Cancer Res 1992;52:3796-800.
Vol. 136, No. 11 Printed in U.S.A.
LETTERS TO THE EDITOR
RE: DEPRESSION, ANTIDEPRESSANT MEDICATION, AND CANCER Several large epidemiologic studies of human subjects have assessed, with conflicting results, a possible connection between depression and cancer incidence, mortality, or outcome. For example, the Western Electric Study continues to show a positive correlation between depressed personality and cancer incidence and mortality after 20 years of follow-up (1), while the Alameda County Study (2) and National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study (3), among others (4-6), have demonstrated no significant association. In contrast, Linkins and Comstock (7) reported a significantly higher rate of development of lung and other cancers in heavy smokers with premorbid depressed mood; Covey et al. (8) suggest that this finding might be attributable, at least in part, to the fact that depressed persons are less likely to quit smoking over time than nondepressed persons. Interestingly, although some of these studies have also assessed the possible contribution of other variables, such as age, alcohol intake, occupation, family history of cancer, body mass, and serum cholesterol (1,2), none have examined the use of antidepressant drugs as a risk factor for cancer development or outcome. Recently, we demonstrated that at doses equivalent to those used in the treatment of human depression, amitriptyline and fluoxetine accelerate the growth rate of cancer in tumor-bearing mice, as well as the development and growth rate of mammary cancer in dimethylbenzanthracene-treated rats (9). We have suggested that these drugs, and structurally similar agents (10), act as copromoters of tumor growth, rather than as true promoters or initiators, by binding to novel intracellular histamine receptors (H|C) present in cell microsomes and nuclei (9, 11, 12) as well as in brain membranes (13). In addition to their stimulation of tumor cell growth, amitriptyline and fluoxetine depress normal lymphocyte mitogenesis (9), suggesting that immune suppression might also contribute to their observed acceleration of tumor growth in vivo. While any relevance to humans remains to be proven, the findings in rodents suggest the possibility that patients with cancer could be adversely affected by the administration of tricyclic antidepressants or fluoxetine, as could subjects with a concomitant heavy exposure to known carcinogens, such as cigarette smoke. We hope that our findings stimulate epidemiologists to examine the
possibility that the drugs used to treat depression, rather than the depression itself, may, in certain circumstances, influence the course or development of human cancer.
1414
REFERENCES
1. Persky VW, Kempthorne-Rawson J, Shekelle RB. Personality and risk of cancer: 20-year follow-up of the Western Electric Study. Psychosom Med 1987; 49:435-49. 2. Kaplan GA, Reynolds P. Depression and cancer mortality and morbidity: prospective evidence from the Alameda County Study. J Behav Med 1988;11:1-13. 3. Zonderman AB, Costa PT, McCrae RR. Depression as a risk for cancer morbidity and mortality in a nationally representative sample. JAMA 1989; 262:1191-5. 4. Hahn RC, Petitti DB. Minnesota Multiphasic Personality Inventory-rated depression and the incidence of breast cancer. Cancer 1988;61:845-8. 5. Weissman MM, Nyers JK, Thompson WD, et al. Depressive symptoms as a risk factor for mortality and for major depression. In: Erlenmeyer-KJmling L, Miller NE, eds. Life-span research on the prediction of psychopathology. Hillsdale. NJ: Lawrence Erlbaum Assoc, Inc. 1986:251-60. 6. Dattore PJ, Shontz FC, Coyne L. Premorbid personality differentiation of cancer and noncancer groups: a test of the hypothesis of cancer proneness. J Consult Clin Psychol 1980:48:388-94. 7. Linkins RW, Comstock GW. Depressed mood and development of cancer. Am J Epidemiol 1990; 132:962-72. 8. Covey LS, Glassman A, Dalack GW. Re: "Depressed mood and development of cancer." (Letter). Am J Epidemiol 1991 ;134:324-5. 9. Brandes LJ, Arron RJ, Bogdanovic RP. et al. Stimulation of malignant growth in rodents by antidepressant drugs at clinically-relevant doses. Cancer Res 1992;52:3796-800. 10. Brandes LJ, Beecroft WA, Hogg GR. Stimulation of in vivo tumor growth and phorbol-ester induced inflammation by N,N-diethyl-2-4-(phenylmethyl)phenoxy-ethanamine HCI, a potent ligand for intracellular histamine receptors. Biochem Biophys Res Commun 1991; 179:1297-1304. 11. Brandes LJ, Bogdanovic RP, Tong J, et al. Intracellular histamine and liver regeneration: high affinity binding of histamine to chromatin, low affinity binding to matrix, and depletion of a nuclear storage pool following partial hepatectomy. Biochem Biophys Res Commun 1992; 184:840-7. 12. Brandes LJ, LaBella FS, Warrington RC. Increased therapeutic index of antineoplastic drugs in combination with intracellular histamine antagonists. J Natl Cancer Inst 1991 ;83:1329-36. 13. Brandes LJ, Bogdanovic RP, Cawker MD, et al.
Letters to the Editor Histamine and growth: interaction of antiestrogen binding site ligands with a novel histamine site that may be associated with calcium channels. Cancer Res 1987;47:4025-3l.
Lome J. Brandes Departments of Medicine and Pharmacology Manitoba Institute of Cell Biology Winnipeg, Manitoba R3E 0V9 Canada AN EDITOR COMMENTS The interesting suggestion by Brandes (I) that antidepressant medication predisposes to cancer in humans adds a new dimension to the debate as to whether depression increases the incidence of cancer. In our long-term follow-up study supported by the National Cancer Institute (grant R35-CA-49761) to screen for Pharmaceuticals that may be carcinogenic (2-4), we have accumulated cancer incidence data of up to 19 years of follow-up of 1,957 patients who filled at least one prescription for amitriptyline, one of the drugs tested in animals by Brandes et al. (5), and of 308 who received imipramine, another heterocyclic antidepressant drug. These drugs were dispensed at the Kaiser Permanente outpatient pharmacy in San Francisco, California, between July 1969 and August 1973, and all patients who obtained prescriptions there during that 4-year period have been followed up for cancer occurrence using the hospital records of the Kaiser Permanente Medical Care Program and the local Surveillance, Epidemiology, and End Results (SEER) program, supplemented by manual review of medical records (4). Expected numbers of cancer cases among users of a particular drug were calculated by applying the age- and sexspecific incidence rates observed in the entire cohort of 143,574 pharmacy users. Observed and expected cases of cancer at each site and all sites combined have been tabulated with follow-up from first prescription dispensing through 1976 initially for amitriptyline, through 1978 for imipramine, and every second year thereafter through 1988 for both drugs. Among the amitriptyline users, 195 developed cancer by the end of 1988. This was not significantly greater than the 182.7 cases expected (standardized morbidity ratio (SMR) = 1.07, 95 percent confidence interval (CI) 0.92-1.23). The standardized morbidity ratio for liver cancer was significantly elevated only in the analysis through 1984, with four cases observed and 1.05 expected, the lower 95 percent confidence limit of the observed cases being 1.09. By 1988, there were still four observed cases, but the expected number had risen to 1.75. In our setting of screening multiple drugs and multiple cancer sites many times, this
1415
single positive finding in 1984 could well be due to chance. The only other significant finding for this drug was a deficit of cases of pancreatic cancer, observed in the two analyses with followup through 1986 and 1988. In both of these, there were zero observed cases, with an upper 95 percent confidence limit of 3.69, the expected numbers being 4.45 and 5.09, respectively. Imipramine users have never shown a significant departure from their expected numbers of new cancer cases at any site. Through 1988, a total of 12 cases of cancer were observed and 15.6 were expected (SMR = 0.77,95 percent CI 0.40-1.34). Thus, these follow-up data do not appear to support a link between human cancer and these two antidepressant drugs used in an ordinary clinical setting, with the caveats that the dosage of the drug or our statistical power may not have been sufficient to detect a small effect. Our follow-up duration should have been more than adequate to detect the co-promoter effect proposed by Brandes. This database may also be used to explore the larger question of whether depression is linked to the subsequent development of cancer. In 19671973, 4,215 patients in this pharmacy cohort received a computer-stored diagnosis of depression from a physician in one of the outpatient clinics in the Kaiser Permanente San Francisco facility (psychiatry clinic not included), of which 3,893, or 92.4 percent, were in the department of medicine. Using the same analytic methodology, we looked at their occurrence of cancer through 1988. For all sites combined, there were 407 cases observed and 432.6 expected (SMR = 0.94, 95 percent CI 0.85-1.04). The only statistically significant departure from expectation was a deficit of breast cancer cases—75 observed and 95.7 expected (SMR = 0.78,95 percent CI 0.62-0.98). Thus, depression itself was not associated with subsequent cancer occurrence in this large cohort. This supports our previous negative findings for self-assessed depression (6). REFERENCES
1. Brandes LJ. Re: Depression, antidepressant medication, and cancer. (Letter). Am J Epidemiol 1992; 136:1414-15. 2. Friedman GD, Ury HK. Initial screening for carcinogenicity of commonly used drugs. J Natl Cancer Inst 198O;65:723-33. 3. Friedman GD, Ury HK. Screening for possible drug carcinogenicity: second report of findings. J Natl Cancer Inst 1983;71:1165-75. 4. Selby JV, Friedman GD, Fireman BH. Screening prescription drugs for possible carcinogenicity: eleven to fifteen years of follow-up. Cancer Res 1989;49:5736-47. 5. Brandes LJ, Arron RJ, Bogdanovic RP, et al. Stimulation of malignant growth in rodents by antidepressant drugs at clinically relevant doses. Cancer Res 1992;52:3796-800.
