Antidepressant Medication Use and Non-Hodgkin’s Lymphoma Risk: No Association

Saira Bahl1, Michelle Cotterchio1,2 , Nancy Kreiger1,2,3 and Neil Klar1,2

1 Division of Preventive Oncology, Cancer Care Ontario, Toronto, Ontario, Canada.
2 Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada.
3 Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.

Received for publication May 24, 2003; accepted for publication March 24, 2004.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Animal and human studies have suggested that antidepressant medications may be associated with several cancers. The authors evaluated the association between antidepressant medication use and the risk of non-Hodgkin’s lymphoma using a Canadian population-based case-control study, the National Enhanced Cancer Surveillance Study. Non-Hodgkin’s lymphoma cases (n = 638) diagnosed in 1995–1996 were identified using the Ontario Cancer Registry, and controls (n = 1,930) were identified from the Ontario Ministry of Finance Property Assessment Database. Antidepressant medication use was ascertained using a self-administered questionnaire. Multivariate logistic regression was used to estimate odds ratios. "Ever" use of antidepressant medications was not associated with non-Hodgkin’s lymphoma risk. The odds ratio for non-Hodgkin’s lymphoma with 25 or more months of tricyclic antidepressant medication use was 1.6; however, this was nonsignificant. Duration or history of use or individual types of antidepressant medications were not associated with non-Hodgkin’s lymphoma risk. These findings do not support an increased risk of non-Hodgkin’s lymphoma with antidepressant medication use.

antidepressive agents; case-control studies; lymphoma, non-Hodgkin; neoplasms

Abbreviations: Abbreviations: ASOR, age- and sex-adjusted odds ratio; CI, confidence interval; SSRI, selective serotonin reuptake inhibitor.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
With the dramatic increase in incidence and mortality rates of non-Hodgkin’s lymphoma over the past 30 years, non-Hodgkin’s lymphoma has become a major health concern in North America. In Ontario, Canada, non-Hodgkin’s lymphoma represents the fifth most common cancer diagnosed in men and the sixth most common in women (1). Apart from immunosuppression and certain chemical agents, very little is known about the etiology of non-Hodgkin’s lymphoma (211). The risk factors examined to date, such as dietary fat, protein, fruit and vegetables, alcohol, and smoking, are either weakly or inconsistently associated with non-Hodgkin’s lymphoma (1220). Immunosuppression does not account for all of the increase in the incidence of non-Hodgkin’s lymphoma in the general population (12, 21). The majority of the cohorts in which non-Hodgkin’s lymphoma rates initially rose were relatively unexposed to immunosuppressive agents or to human immunodeficiency virus, particularly since the non-Hodgkin’s lymphoma incidence rates were first noted to rise as early as the mid-1960s (in Ontario), long before the acquired immunodeficiency syndrome epidemic that began in the 1980s (12). The increased risk of non-Hodgkin’s lymphoma with heavy exposure to pesticides in the farming and agriculture industries may explain only some of the overall rise in non-Hodgkin’s lymphoma (912), since there are concomitant increases in non-Hodgkin’s lymphoma in urban populations, where exposure likely includes only household pesticide use and food consumption (22). Attention must be directed toward other potential risk factors not yet studied.

Few experimental studies and one epidemiologic study have suggested that antidepressant medications may be associated with the occurrence of non-Hodgkin’s lymphoma (2325). The only study to evaluate antidepressant medication use and non-Hodgkin’s lymphoma risk consisted of 30,807 antidepressant medication users in Denmark and reported an increase of non-Hodgkin’s lymphoma among users of tricyclic antidepressant medications; the standardized incidence ratio was 2.5 (95 percent confidence interval (CI): 1.4, 4.2) for those with five or more prescriptions of tricyclic antidepressants. A dose-response relation was apparent as prescriptions of tricyclic agents increased from occasional (one prescription: standardized incidence ratio = 0.8) to periodic (2–4 prescriptions: standardized incidence ratio = 1.4) to regular (≥5 prescriptions: standardized incidence ratio = 2.5) use.

Given the possible association between antidepressant medications and non-Hodgkin’s lymphoma and the increase in use of antidepressant medications since the 1970s, further investigation in this area is warranted (26). Our study evaluated the association between antidepressant medication use and the risk of non-Hodgkin’s lymphoma using a population-based case-control study in Ontario.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Cases and controls
The study participants (12 cancer types and population-based controls) and methods were those of the Ontario component of the National Enhanced Cancer Surveillance Study (27). Only the Ontario data were analyzed because information on antidepressant medication use was not collected at the other study sites.

Cases identified using the Ontario Cancer Registry were 20–74 years of age, diagnosed with a primary non-Hodgkin’s lymphoma between 1995 and 1996 (International Classification of Diseases, Ninth Revision, codes 200 and 202), and resided in Ontario at the time of diagnosis (28). Cases were selected and histologically confirmed by review of pathology reports. The 1995 Ontario Ministry of Finance Property Assessment Database formed the sampling frame for selection of controls. This database contains the name, address, sex, and year and month of birth for all homeowners and tenants of Ontario. This file was used to randomly select controls for sex and 5-year age groups similar to those of all cancer cases combined. The controls were selected so that at least a 1:1 control:case ratio for any cancer site was secured across all age and sex strata. Consequently, for some less common cancers such as non-Hodgkin’s lymphoma, there were multiple controls per case. To maximize power, we included all available controls in each sex and 5-year age stratum. Comparing the control with the non-Hodgkin’s lymphoma distribution by sex and across the 5-year age strata yielded an approximate 3:1 control:case ratio. The control:case distribution was similar across all ages and for both sexes.

Data collection
Physicians were identified from pathology reports and sent a letter to obtain consent to contact the patients (following ethics approval obtained from the University of Toronto, September 1994). Cases and controls were mailed an explanatory letter and a self-administered questionnaire. Postcard reminders were mailed after 2 weeks, second questionnaires and reminder letters were mailed at 4 weeks, and telephone follow-up calls were conducted at 6 weeks. The questionnaire asked about demographic and socioeconomic information, employment, lifetime residential and occupational histories, smoking history, exposure to environmental tobacco smoke, alcohol consumption, dietary habits, physical activity, reproductive history, medication use, and history of depression. Information on duration, dosage, timing, and type of antidepressant medication was collected. Subjects were asked: "Have you ever taken antidepressants for at least 2 weeks at any time in your life?" (a list of 11 antidepressant medications and an "other" category was provided). If subjects responded "yes," they were asked to provide the name, dosage, and dates started and stopped for each antidepressant medication used.

Data analysis
Descriptive statistics for all study variables were examined by case-control status. Multivariate logistic regression was used to obtain odds ratio estimates and associated 95 percent confidence intervals (29). These odds ratio estimates were obtained for "ever" antidepressant medication use, duration, and time since first and last use of antidepressant medications. Multivariate logistic regression analyses were limited to variables selected from the study questionnaire that seemed most likely to confound the association between antidepressant medication use and the risk of non-Hodgkin’s lymphoma. These included household income, body mass index, self-reported depression (i.e., "feel depressed for at least 2 weeks" and diagnosis of clinical depression), exposure to chemicals, smoking, and dietary factors (dietary fat and protein and alcohol consumption) (table 1). Dietary factors were categorized as tertiles or quartiles on the basis of the distributions in the controls. Confounding was assessed by the 10 percent change in the odds ratio estimate method (30). For all regression models, the interactions between age, sex, or depression (listed in table 1) and antidepressant medication exposure ("ever" use, duration of use, time since first and last use) were evaluated for statistical significance based on the Wald chi-square statistic. All hypothesis tests were two sided and were conducted using a 5 percent type I error rate. Odds ratios for "ever" use of antidepressant medications were also estimated after stratifying by sex and history of depression to explore their potential as effect modifiers.


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TABLE 1. Frequency distribution, age- and sex-adjusted odds ratio of non-Hodgkin’s lymphoma, and 95% confidence interval for participant characteristics, Ontario, Canada, 1995–1996
 
"Ever" use of antidepressant medications was obtained for all antidepressant medication classes combined, for each main class (tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors, and atypical agents), and for specific types of antidepressants (e.g., fluoxetine and amitriptyline). Specific types were analyzed if there were at least 10 users (cases and controls). Tranquilizers, antipsychotics, antiepileptics, or anticonvulsants were not considered to be antidepressant medications. Medication use within the 6-month period prior to diagnosis of cases or the index date for controls was treated as "no use." The referent date for controls was defined as October 15, 1995, which was the midpoint of the range of diagnosis dates for cases. Never use of antidepressant medications was the referent category for all analyses. Missing data were minimal for exposure variables and for most potential confounders. A separate analysis with and without missing data was carried out using age- and sex-adjusted models for comparison. In the former analysis, missing data were included as a separate category for each variable and, in the latter case, listwise deletion (removal of subjects with missing data from the analysis) was used.

A total of 1,158 non-Hodgkin’s lymphoma cases were identified, of which 298 were ineligible, 62 could not be located, 58 were physician refusals, and 17 physicians and patients could not be contacted. Of the remaining 723 subjects, there were 85 subject refusals. A total of 638 (306 males, 332 females) cases returned completed questionnaires, resulting in a case response rate of 88 percent (638/723). Among controls, the response rate was 79 percent (1,930/2,446).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Cases were more likely than controls to be previous smokers (cases: 46.1 percent, controls: 38.6 percent), less likely to be current smokers (cases: 14.1 percent, controls: 19.8 percent), and more likely to be clinically obese (>27 kg/m2) (cases: 36.4 percent, controls: 31.2 percent) (table 1). Similar distributions of cases and controls were noted for household income, education, pack-years of smoking, "feel depressed for at least 2 weeks," and diagnosis of clinical depression, but a significantly lower proportion of cases was found in the "middle" household income category (age- and sex-adjusted odds ratio (ASOR) = 0.7, 95 percent CI: 0.5, 0.9).

Cases were more likely than controls to report chemical exposure, wood dust, and pesticides. A significantly lower proportion of cases consumed 4.5 or more drinks per week compared with controls (cases: 27.4 percent, controls: 31.4 percent; ASOR = 0.7, 95 percent CI: 0.6, 0.9). In the maximum quartile of dietary fat (≥399.6 g/week), the age- and sex-adjusted odds ratio was 2.1 (95 percent CI: 1.6, 2.9), and the proportion of cases that consumed high levels of dietary fat was reportedly larger than that of controls (cases: 25.4 percent, controls: 19.7 percent). With dietary intake of protein, a slightly higher proportion of cases was in the highest quartile.

Regression models were adjusted for only age and sex because no confounders were identified. In multivariate regression models, interactions between depression and antidepressant medication use or between sex and antidepressant medication use were nonsignificant. Equivalent conclusions were reached when odds ratios of antidepressant medication use were stratified by depression or sex.

There was little difference between the proportions of cases and controls that reported using any antidepressant medications (cases: 9.2 percent, controls: 10.4 percent) (table 2). "Ever" use of antidepressant medications was not found to be associated with non-Hodgkin’s lymphoma risk (ASOR = 0.9, 95 percent CI: 0.6, 1.2) (table 2). Similar results were found with each class of antidepressant medication. The odds ratio estimates were close to one for tricyclic antidepressants (ASOR = 0.8, 95 percent CI: 0.5, 1.3), for SSRIs (ASOR = 1.1, 95 percent CI: 0.6, 1.9), and for atypical agents (ASOR = 1.0, 95 percent CI: 0.3, 3.9).


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TABLE 2. Frequency distribution, age- and sex-adjusted odds ratio of non-Hodgkin’s lymphoma, and 95% confidence interval for "ever" use of any and different classes of antidepressant medications, Ontario, Canada, 1995–1996
 
Of 17 antidepressant medications reported in our study, there were eight tricyclic antidepressants (amitriptyline, doxepin, desipramine, Ludiomil (Ciba-Geigy Corp. USA, Ardsley, New York), nortriptyline, imipramine, clomipramine, and trimipramine), four SSRIs (fluoxetine, paroxetine, sertraline, and fluvoxamine), two monoamine oxidase inhibitors (moclobemide and phenylzine), and three atypicals (trazodone, venlafaxine, and nefazodone). Amitriptyline, imipramine, clomipramine, sertraline, and trazodone were each associated with a nonsignificant decreased risk of non-Hodgkin’s lymphoma (ASORs ranged from 0.2 to 0.7) (table 3). The risk of non-Hodgkin’s lymphoma was elevated by 40 percent with the use of fluoxetine, although the 95 percent confidence interval included one (ASOR = 1.4, 95 percent CI: 0.8, 2.4).


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TABLE 3. Frequency distribution, age- and sex-adjusted odds ratio of non-Hodgkin’s lymphoma, and 95% confidence interval for "ever" use of specific antidepressant medication, Ontario, Canada, 1995–1996
 
No pattern was observed with duration of any antidepressant medication use and non-Hodgkin’s lymphoma risk (table 4). A 60 percent increase in non-Hodgkin’s lymphoma risk was found among cases that used tricyclic antidepressant medication for 25 months or more, but this increase was not significant. While a nonsignificant twofold increase in non-Hodgkin’s lymphoma risk was found with the use of SSRIs for 5 months or less and for 6–17 months, no pattern was observed with increasing duration.


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TABLE 4. Frequency distribution, age- and sex-adjusted odds ratio of non-Hodgkin’s lymphoma, and 95% confidence interval for duration and time since first and last use of antidepressant medication, Ontario, Canada, 1995–1996
 
No pattern was observed with time since first use and non-Hodgkin’s lymphoma risk. The times since last use of antidepressant medications for 1–3 months (tertile 1) and for 4–112 months (tertile 2) were nonsignificantly associated with a 20–30 percent increased risk of non-Hodgkin’s lymphoma. Beyond this period, the odds ratio estimate was reduced (ASOR = 0.5, 95 percent CI: 0.2, 1.1).

Comparison of the odds ratios with and without a "missing" category produced similar results (data not shown), and the proportion of missing data was small for these variables. Concerns for participation bias may therefore be reduced. It is well known that the inclusion of a "missing" data category may bias results and inadequately account for confounding (30).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
No association was apparent between antidepressant medication use and non-Hodgkin’s lymphoma risk. To date, only one other epidemiologic study has evaluated whether there is an association between antidepressant medication use and non-Hodgkin’s lymphoma risk (25). The large population-based cohort study by Dalton et al. (25) reported a statistically significant 2.5-fold increase in risk of non-Hodgkin’s lymphoma with five or more prescriptions of tricyclic antidepressant medications. Interestingly, of the many cancer sites evaluated, only non-Hodgkin’s lymphoma was significantly associated with antidepressant medication use (25). In the study by Dalton et al. (25), the use of prescription data in Denmark permitted analysis by increasing dose, measured as the number of antidepressant medication prescriptions. Prescription data were not available in our study, and a large portion of dosage information was missing or incomplete in our questionnaire; therefore, a dose-response relation could not be evaluated beyond the scope of increasing duration. The definitions of tricyclic and tetracyclic agents in the cohort study by Dalton et al. (25) covered pharmacologic drugs similar to those defined as tricyclic antidepressants in our study, including imipramine, clomipraimine, trimipramine, amitriptyline, nortriptyline, and doxepin. Other tricyclic antidepressants (which were not available for study in our analysis and/or not marketed in Canada) in the study by Dalton et al. (25) were also evaluated (opipramol, lofepramine, protriptyline, dosulepin, amoxapine, maprotiline, and mianserin). These differences render our tricyclic antidepressant findings not comparable to those of the study by Dalton et al. (25).

Our study does not support an association between "ever" use of SSRIs or increased duration of SSRI use and non-Hodgkin’s lymphoma risk. Despite the paucity of epidemiologic data regarding SSRIs and non-Hodgkin’s lymphoma risk, several experimental studies have evaluated this hypothesis. Serafeim et al. (23) reported that fluoxetine, paroxetine, and citalopram promoted the growth of in vitro non-Hodgkin’s lymphoma, specifically Burkitt’s lymphoma in serotonin-driven apoptosis experiments. It has also been suggested that tricyclic antidepressants and SSRIs have the opposite effect on other immune cells important in apoptosis (31, 32). The tricyclic antidepressant structural analog, carbamazepine, was found to be associated with a diagnosis of non-Hodgkin’s lymphoma in one patient whose disease went into remission after withdrawal from the drug (24). The authors suggested that the development of non-Hodgkin’s lymphoma may be related to the depression of immune cells well known to occur in patients treated with carbamazepine. In monkeys, fluoxetine was shown to lower antibody levels (33). The production of antibodies is a specific immune response against infections and other foreign pathogens (34). Therefore, given this negative immunoregulatory effect of fluoxetine and its inhibitory effect on apoptosis, it is plausible that SSRIs could play a role in initiating or enhancing already present non-Hodgkin’s lymphoma tumors. These findings are based on in vitro animal studies and case reports and, as such, they cannot be confidently extrapolated to humans; nonetheless, they provide insight into a possible biologic mechanism of some antidepressant medication types and encourage further studies to explain the controversy of the cancer-antidepressant medication hypothesis.

As animal data have suggested that antidepressant medications may act to promote tumor growth, it has been suggested that recent use of antidepressant medications may be associated with cancer occurrence (35). The effect of recent use of antidepressant medications and latency on non-Hodgkin’s lymphoma risk has not been studied previously. Our study does not support the promoter hypothesis because no association was observed between non-Hodgkin’s lymphoma risk and time since last use of antidepressant medications. We did not observe a latency effect regarding antidepressant medications on non-Hodgkin’s lymphoma risk.

Consistent with other studies (911), our study found that non-Hodgkin’s lymphoma was positively associated with chemical exposures, which strengthens the internal validity and generalizability of these findings. Depression was not found to be a risk factor for non-Hodgkin’s lymphoma nor did it confound the cancer-antidepressant relation in this study. While it has been suggested that depression results in immunosuppression, subjecting the individual to a greater risk for cancer, to date, the evidence is inconsistent and inconclusive. Four studies have reported a significant positive association between depression and cancer (3639), while five studies have reported no association or, at best, a weak positive one (4044). Two studies that examined non-Hodgkin’s lymphoma reported no association (39, 44).

The overall strength of our study was in its population-based design. Cases were obtained from a population-based cancer registry, and controls were drawn from the corresponding population using a population-based sampling frame. The completeness of the Ontario Cancer Registry is high, estimated at 96 percent for both males and females over the period of 1964–1996 (1).

Inaccurate recall of past antidepressant medication may not have been a serious concern in the present study for several reasons: Recall bias may be reduced because participants were unaware of any hypotheses concerning cancer and antidepressant medication use, and the stated purpose of the National Enhanced Cancer Surveillance Study was to investigate environmental exposures for a wide range of cancers. In addition, a study based on the National Enhanced Cancer Surveillance Study data assessed the misclassification of self-reported antidepressant medication use among females; high agreement between subject- and physician-reported "ever" use of antidepressant medication and moderate agreement with duration and date of first use were reported (45). This study also suggested that recall bias was unlikely in the reporting of "ever" antidepressant medication use. Another case-control study of breast cancer reported moderate sensitivity and high specificity of self-reported duration of antidepressant medication use compared with pharmacy records for all women by case-control status for a 6-month, 2-year, or 8-year period (46). No differences were reported between cases and controls. While these findings provide some reassurance about the absence of recall bias, the possibility of this type of bias cannot be excluded definitively.

The collection of information regarding the specific types of antidepressant medications was a strength of this study, as recent experiments have reported that specific antidepressants were differentially associated with non-Hodgkin’s lymphoma (23). Information on general medication history, however, was not available for this study; therefore, we could not control for concomitant drug use.

We did not collect information regarding immunosuppression, and it is known that immunosuppression (e.g., immunosuppressive therapy, human immunodeficiency virus/acquired immunodeficiency syndrome, or certain inherited immune deficiencies) may lead to non-Hodgkin’s lymphoma. Since only small proportions of non-Hodgkin’s lymphoma tumors are caused by these factors, lack of this information may not be a substantial concern with respect to confounding (3, 47).

In conclusion, our findings do not support an increased risk of non-Hodgkin’s lymphoma with use of antidepressant medications. Any future studies should be sufficiently powered to investigate each of the classes and types of antidepressant medications and should attempt to obtain dosage information.


    ACKNOWLEDGMENTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
This research was performed within the context of the Enhanced Cancer Surveillance Project, sponsored by the Laboratory Centre for Diseases Control, Health Canada (contract H4078-3-C119/01-SS).

The authors thank Margaret Sloan for her technical assistance.


    NOTES
 
Correspondence to Dr. Michelle Cotterchio, Division of Preventive Oncology, Cancer Care Ontario, 620 University Avenue, Toronto, Ontario M5G 2L7, Canada (e-mail: michelle.cotterchio{at}cancercare.on.ca). Back


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 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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