Antidepressant Prescription and Risk of Lung Cancer: A Nationwide Case-Control Study

• Abstract
• Introduction
• Methods
• Database
• Study subjects and design
• Identification of antidepressant exposure
• Confounding factors/assessment of health status
• Statistical analysis
• Results
• Characteristics of the case and control groups
• Association of antidepressants exposure dosage and risk of lung cancer
• Discussion
• Antidepressants and lung cancer
• Classes of antidepressant
• Bupropion and lung cancer
• Prevalence of depressive disorder
• Strengths and weaknesses
• Conclusions
• Acknowledgments
• References

Abstract

Introduction In recent decades, concern about safety of antidepressants has been raised but the risk between antidepressants and lung cancer has not yet been established.

Methods A case-control study was conducted by using a nationwide database in Taiwan. The case groups were new onset lung cancer diagnosis during 1999–2008 and age- and gender-matched controls were selected among those without any cancer. The cumulative exposure dose before the lung cancer diagnosis was added and risks were calculated according to the levels of defined daily dose and classes of antidepressants.

Results A total of 39,001 individuals with lung cancer and 189,906 individuals without lung cancer between 1999 and 2008 were included in the analysis. Antidepressants, of any class, were not associated with elevated risks for lung cancer with the exception of bupropion at high exposure levels (odds ratio=4.81, 95% confidence interval=1.39–16.71).

Discussion Antidepressant prescription was not associated with elevation of lung cancer incidence using a nationally representative sample. The elevated risk for lung cancer with bupropion at high doses may be a bias by indication and warrant longitudinal investigation.

Introduction

Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) are commonly prescribed for the treatment of psychiatric conditions. In recent decades, the prescription of antidepressants has increased dramatically in both Western and Eastern countries [1] [2] [3] [4]. Preclinical studies suggest that some antidepressant agents may possess tumor-initiating and/or tumor-promoting properties [5] [6] [7] [8]. For example, in studies of in vivo rodent models, TCAs and SSRIs have been reported to promote tumor growth [7]. Studies documenting an association between antidepressant exposure and carcinogenic effect have produced findings that are mixed and often contradictory. For example, preclinical studies suggest that antidepressants may promote tumor growth via growth-regulatory intracellular antihistamine receptors [9] or inhibition of apoptosis [10]. However, other studies have inconsistently reported negative findings and tumor-inhibiting effects of antidepressants. In addition, there is an absence of consistent findings in clinical populations [11] [12] [13].

A prior systematic review of the association between carcinogenesis and TCA exposure reported that although there is some suggestive evidence, it is insufficient to conclude that there exists an association between TCA exposure and carcinogenesis [5]. Similarly, a population-based cohort study in Finland reported a weak, nonlinear, non-dose-dependent association between SSRI exposure and increased breast cancer incidence, as well as non-SSRI antidepressant exposure and colon cancer incidence [14]. The authors of the foregoing study suggest that SSRIs may elevate the risk of breast cancer via their effect on prolactin secretion. However, a recent meta-analysis did not identify a clinically meaningful association between antidepressant use and the development of breast cancer [15]. Furthermore, several case-control and preclinical studies suggest that antidepressants may have a protective effect. For example, antidepressants may be protective against colorectal cancer through inhibition of cellular proliferation [16] [17] [18].

Lung cancer is the most common cause of cancer-related death worldwide [19]. Studies investigating the risk of lung cancer associated with exposure to antidepressants have reported inconsistent findings. Based on in vitro and in vivo bioinformatics studies, clomipramine, a TCA, was demonstrated to inhibit small-cell lung cancer activity in preclinical models [20] and amitriptyline downregulates coenzyme Q10 biosynthesis in non-small-cell lung cancer cell line and might be used as a potential antitumoral oxidative [21]. A previous population-based study in the United Kingdom (UK) found a reduced risk for lung cancer with SSRI use (odds ratio [OR]=0.59, 95% confidence interval [CI]=0.41–0.86) [22]. However, the protective effect of SSRI treatment was limited to those receiving treatment for more than 1 year and potential confounding variables (e. g., depression, smoking) were not adjusted for in the analysis. In addition, in the foregoing study, TCA use was associated with a nonstatistically significant moderately elevated risk (OR=1.23, 95% CI=0.96–1.58). In contrast, a nested case-control study in a large, nationally representative sample population from the UK’s electronic medical records database reported elevated risks for lung cancer with SSRI or TCA treatment (OR=1.27, 95% CI=1.16–1.38 and OR=1.45, 95% CI=1.31–1.60, respectively) initiation more than 1 year before index date, but not SNRI treatment [23]. In a retrospective clinical study aimed at metastatic small-cell lung cancer patients, both SSRIs and clomipramine showed no statistically significant benefit of overall survival [24]. Furthermore, there are differences between East Asian and Western populations in risk factors, illness onset, and trajectory that may influence any putative moderation/mediation effect of antidepressants on lung cancer risk. For example, individuals with lung cancer in Asia are more likely to be younger, less likely to smoke, and are more likely to have a better prognosis [25]. To our knowledge, no previous study has investigated the possible association between antidepressant prescription and elevated risk for lung cancer. Herein, we conducted a case-control study using a Taiwan’s National Health Insurance Research Database (NHIRD) to assess the association between antidepressant prescription and incidence of lung cancer.

Methods

Database

As reported elsewhere, Taiwan’s National Health Insurance (NHI) program is a state-operated health program that was implemented in 1995 and covers more than 99% of the Taiwanese national population [26]. The NHIRD provides patient demographics and medical records (e. g., diagnoses, drug prescriptions, and claims). All the diagnoses reported in the NHIRD are coded using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). All the patient records were anonymized prior to analysis. This retrospective study was approved by the Chiayi Chang Gung Memorial Hospital institutional review board.

Study subjects and design

All individuals enrolled in the NHI program during the study period (i. e., January 1, 1997, to December 31, 2008) with complete medical records (e. g., date of death, date of exit from the database, where applicable) and without history of cancer prior to study period (i. e., between January 1, 1997, and December 31, 1998) were eligible for inclusion in the study. Inclusion criteria for the cohort of individuals with lung cancer included primary diagnosis of lung cancer (i. e., ICD-9-CM code: 162) with hospitalization during the study period. The diagnosis of lung cancer was confirmed by the presence of a record in the system of “catastrophic illness” certificates, which are issued by the Taiwan government and grant patients free health care for qualifying illnesses and/or related conditions. As the requirements for catastrophic illness certificates are stringent and require not only a clinical diagnosis but also documentation of lung cancer pathology, catastrophic illness records were used to further validate the incidence of primary lung cancer in the study population.

We used an incidence density sampling method for each lung cancer case and randomly selected 5 age- and gender-matched controls in order to maximize the power of statistical analysis [27]. The control group is without any cancer diagnosis at the index date of lung cancer cases from the NHI dataset of 1 million people, which was randomly culled from the entire NHI population.

Identification of antidepressant exposure

The specific metric that best quantifies antidepressant exposure remains unresolved. The most common methodology uses was the defined daily dose (DDD). Development of DDD methodology has been a major advance in attempts to promote standardized comparisons [28]. The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults. Antidepressants’ DDD was quantified according to the World Health Organization Collaborating Centre for Drug Statistics Methodology. Antidepressant exposure was assessed and calculated using the cumulative dosage of prescription we extracted from the NHIRD during the study period and turned into total DDD exposure. The exposure to all antidepressants 1 year immediately before the index date in the lung cancer group or 1 year immediately before January 1 of their inclusion year in the control group was excluded from the analysis to minimize protopathic bias. The DDD was stratified to 4 graded exposure levels: (1) 28–83 DDD, (2) 84–167 DDD, (3) 168–335 DDD, and (4)≥336 DDD. Antidepressants were categorized as SSRIs (e. g., fluoxetine, fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline), SNRIs (e. g., duloxetine, venlafaxine, and milnacipran), TCAs (e. g., amitriptyline, clomipramine, imipramine, dothiepin, doxepin, maprotilinem, and melitracen), monoamine oxidase inhibitors (MAOIs), mirtazapine, trazodone, or bupropion.

Confounding factors/assessment of health status

Potential confounding medical conditions, including type 2 diabetes mellitus (T2DM), hypertension, hypercholesterolemia, pneumonia, pulmonary tuberculosis (TB), asthma, chronic obstructive pulmonary disease (COPD), coal worker pneumoconiosis, asbestosis, toxic effect of arsenic, human immunodeficiency virus (HIV), and smoking were adjusted for in the analysis. Furthermore, prescription of medications known to moderate the risk for lung cancer (e. g., aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], and statins) was controlled for in the analysis [29] [30] [31] [32] [33]. Potential confounding variables including socioeconomic status (SES) was adjusted for by using income and urbanization of living area as proxies in the model. Urbanization was quartiles by using human development index, a well-established socioeconomic development indicator with summary measure of income, health, and education index [34].

Statistical analysis

We used a conditional logistic regression model to categorically assess lung cancer risk by the DDD. The OR and 95% CI were calculated and reported using models unadjusted and adjusted for covariates (e. g., SES, medical comorbidities, environment exposure to toxins, aspirin, NSAIDs, and statins). χ2-tests for categorical variables and the t-test for continuous variables were used for comparing demographics, medical diseases, and the use of medications. Cox proportional hazard regression models were used to examine the risk of exposure to each type of mood stabilizer associated with outcome after adjusting for age, sex, comorbidities, and the concomitant use of other psychotropic agents. The statistical significance of relationships was assessed using a 95% CI, or a p-value<0.05. All analyses were conducted using the SAS version 9.2 software package (SAS Institute, Cary, NC, USA).

Results

Characteristics of the case and control groups

Data from 39,001 individuals with lung cancer and 189,906 individuals without lung cancer were included in the analysis herein ([Fig. 1]). As seen in [Table 1], individuals with lung cancer were more likely to have middle income when compared to age- and gender-matched controls. Individuals with antidepressant prescriptions were more likely to live in areas of moderate urbanization (quartiles by human development index). In the lung cancer group, 6.41% had been exposed to SSRIs, 6.67% to TCAs, and 10.3% to MAOIs. In the control group, 5.96%, 6.23%, and 7.43% had been exposed to SSRIs, TCAs, and MAOIs, respectively. As seen in [Table 2], individuals with lung cancer were significantly more likely to have a diagnosis of major depressive disorder (MDD), T2DM, hypertension, pneumonia, pulmonary TB, asthma, COPD, and coal worker pneumoconiosis, to smoke, and to have exposure to arsenic and NSAIDs. Individuals with lung cancer were less likely to have a diagnosis of hypercholesterolemia when compared to controls. No differences were found with respect to HIV status, asbestosis, or exposure to aspirin or statins.

Association of antidepressants exposure dosage and risk of lung cancer

No statistically significant elevated risks for lung disease were found in any category of antidepressant class (e. g., SSRIs, SNRIs, TCAs, MAOIs, mirtazapine, trazodone, and bupropion) or dosage in the unadjusted model ([Table 3]). After the adjustment, the results remained nonstatistically significant except with≥336 DDD bupropion (adjusted OR=4.81, 95% CI=1.39–16.71).

Discussion

Antidepressants and lung cancer

This is the first study conducted in an Asian population primarily investigating the risk for lung cancer in antidepressant users within a population-based database. The study herein did not identify a statistically significant difference in risk for lung cancer with any class of antidepressants, except with bupropion at higher doses (i. e.,≥336 DDD).

The relationship between antidepressant use and risk for lung cancer had been reported previously in a UK-based study [22]. Toh et al. reported that the use of SSRIs did not increase the lung cancer risk but instead might be associated with a reduced risk. However, the study also reported a marginally elevated risk of lung cancer with TCA use. A limitation of the study was the lack of adjustment for the duration of smoking. Furthermore, Toh et al. validated lung cancer diagnoses by reviewing medical records only. In our study, smoking-related disorders such as COPD were adjusted for in the analysis, and the diagnosis of lung cancer was further validated by the catastrophic illness database, which documents pathological and/or imaging evidence. Another population-based study of antidepressant use and risk for 20 different cancers in a Finland population reported no significant association between lung cancer and SSRIs or non-SSRI antidepressants at any DDD [14]. A methodological limitation of the foregoing study, however, is the absence of adjusting for concurrent medical conditions (e. g., asthma, COPD, pneumonia, and pulmonary TB).

Classes of antidepressant

The current study provided preliminary benefit/risk findings in different classes of antidepressants among an Asian population. In this population-based case-control study, antidepressant exposure of various classes or doses did not elevate risk for lung cancer. We did not find a dose-dependent association between antidepressant exposure and risk for lung cancer, either. However, though not significant, most classes of antidepressants showed trends of decreased risk while SNRIs showed increased risk. Different types of TCA, SSRI, or SNRI administered may have led to discordant outcome toward cancer progression and toward different cancer type and might need to be investigated individually [24]. In an in vitro study comparing the antitumor effects of antidepressants in human hepatocellular carcinoma cells, SSRIs and the SNRI duloxetine showed marked dose-dependent antitumor effects but another SNRI, milnacipran, had no effect on cell viability [35]. A nested case-control study using a UK population-representative database also investigated the influence of antidepressants on risk for cancer [23]. After adjustment, SSRI (OR=2.26, 95% CI=2.00–2.54) or TCA (OR=2.93, 95% CI=2.60–3.30) but not SNRI treatment was associated with a higher lung cancer risk. When the effect of duration of antidepressant therapy was considered, the risk for lung cancer was elevated with SSRI or TCA treatment with any duration of exposure. The possibility for reverse causality cannot be ruled out, however, as SSRI and TCA initiation within the year before lung cancer diagnosis should be considered as some early symptoms of lung cancer such as poor appetite and body weight loss overlap with depressive symptoms. Herein, to minimize protopathic bias, we excluded antidepressants exposure in the year preceding the index date. Furthermore, the foregoing analysis in the UK population-based case study used the location of the patient’s general practitioner to proxy SES and other potential environmental exposures, which might not be as representative as using insurance premiums. In addition, the analysis did not have pathological evidence of cancer.

Bupropion and lung cancer

In an in vitro study by using cells of the human neuroblastoma cell line, treatment with high concentration bupropion significantly induced the mRNA expression of the death receptors 4 (DR4) and DR5. DR4 and DR5 played key roles in the transduction of extrinsic apoptotic signals through the activation of the caspase cascade, particularly in tumor cells [36]. However, no studies so far have found bupropion to have elevated cancer risk. The elevated risk for lung cancer with bupropion treatment at high doses noted in the current study may be a bias by indication, as bupropion is also used to aid smoking cessation by improving abstinence rates, depressive symptoms, and quality of life [37]. Around 8% people in our bupropion group were smokers compared to 0.3–1% in other classes of antidepressants. Because smoking is a known risk factor for the development of lung cancer, those using high doses of bupropion may also be smokers [38]. Besides, only 5 subjects in the cancer group and 5 in the control group were exposed to a high DDD of bupropion. Further study of larger sample size to test the relationship might be needed.

Prevalence of depressive disorder

Lifetime prevalence for MDD varies widely across countries, ranging from 1.1% to 19.0% [39] [40] [41], but the prevalence of depression in the current study is relatively low. We found that the lung cancer group had 4% prevalence of depressive disorder while the control group had 3.6%, which is similar to other epidemiologic studies in Asia. The prevalence of depression found in the previous community study in Asia is much lower than in Western countries [41] [42]. Across the Asia Pacific region, rates of MDD in the previous year ranged from 1.7% to 6.7%, with a median lifetime rate of 3.7% [41]. In a population-based NHI study investigating the prevalence of treated MDD in Taiwan, the cumulative treated prevalence was 17.24 per 1000 at the end of 2003 [43]. Possible explanations include depression was underdiagnosed and undertreated in Taiwan, social stigma leads to a denial of symptoms or underreporting of previous depressive episodes, or depressive syndromes may manifest differently in culture (e. g., as neurasthenia or somatization) [43] [44] [45]. Besides, depressive disorder is significantly more prevalent in the lung cancer group than in the control group in our study. In a cross-sectional study using a national patient sample provided by the South Korean NHI, they found patients with lung cancer were the most prone to experience depression among the 10 most prevalent cancers in South Korea [46]. Higher levels of psychological distress, health-related stigma, and poorer quality of life were reported in lung cancer patients than in other types of cancers [47] [48].

Strengths and weaknesses

To our knowledge, this is the first national population-based study investigating the relationship between antidepressants and lung cancer in Asia. We examined data from the NHIRD, which includes more than 99% of the total national population of Taiwan. It not only provides a large sample size but also has a low risk for selection bias. Furthermore, the diagnosis of lung cancer in our study was not only ascertained from the NHI database but also further validated by the catastrophic illness system, which includes documentation of lung cancer pathology. Lung cancer is a disease thought to develop via a protracted asymptomatic period. Early symptoms of lung cancer may overlap with depressive symptomatology, including but not limited to decreased appetite or energy, and may lead to the prescription of an antidepressant. Thus, the incident diagnosis of lung cancer may be confounded by the temporality of treatment for mood symptoms associated with lung cancer. The exclusion, herein, of individuals with antidepressant exposure 1 year prior to the index date may mitigate the risk for the foregoing protopathic bias. However, further investigation is required to ascertain the differential risks for lung cancer with disparate antidepressant treatments. There are several limitations to our analysis pertaining to our study methodology. First, there is no lifestyle information in the database, although we attempted to adjust for possible lifestyle differences by reported income and level of urbanization of living area. Second, the reported prevalence of smokers in our study population (i. e., 0.30% in the case group and 0.15% in the control group) is lower than expected and thus may have led to an underestimation of the influence of smoking on risk for lung cancer in antidepressant users. Around 26–31% of indigenous Taiwanese were found to be current smokers in a nationwide telephone survey for the years 2005–2008 [49]. It is always a major limitation of the current database because physicians would not regularly record smoking as their diagnosis in the system, though they do have smoking-related codes in the medical system, such as ex-smoker, smoker’s cough, tobacco smoker, or smoking-associated melanosis. The reported prevalence of smokers in the current study could not represent the actual smoking rate in Taiwan entirely unless incorporated with other source of information such as Health Promotion Administration. However, we attempted to reduce this bias by controlling for smoking-related illnesses such as COPD. Third, the use of antidepressants was proxied by prescription records, but there was no mechanism to verify that patients adhered to the prescribed treatment. This might inflate estimates of antidepressant usage and underestimate the true influence of antidepressants toward lung cancer. Fourth, lung cancers (e. g., small-cell, non-small-cell) have different pathogenesis and causes [50]. It is possible that antidepressants influence differently on the way and risk of those tumor types. For example, within non-small-cell lung cancer, amitriptyline had potential of antitumoral oxidative therapy by inducing a dose-dependent decrease in coenzyme Q levels in tumor cells [21] while imipramine and clomipramine might be played as potent inducers of cell death in small-cell lung cancer cells through activation of stress pathways [20]. Lumped all lung cancers together when examining risk factors, such as smoking or use of antidepressants should be regarded in caution. However, the ICD-9-CM codes used in current study made it difficult to differentiate lung cancer from small-cell to non-small-cell. By using the new version of illness classification system in the future, subgroup analysis about the risk of antidepressants in different tumor types might be possible.

Conclusions

In the current population-based study, antidepressant prescription did not elevate the risk for lung cancer with the exception of bupropion at high doses. This study has suggested its safety between antidepressant prescription and risk for lung cancer, in a representative sample from an Eastern country. Despite the limitations of the case-control study and the database, we believed the findings can provide practical information for clinicians to discuss with their patients when prescribing antidepressants. However, the possible mechanism and the effect of bupropion warrants more research. Given the high prevalence of antidepressant use in the present days, future studies should use a more rigorous methodology to control for medication adherence, lung cancer types, and staging or lifestyle and to evaluate specific biological mechanisms between antidepressants and cancer risk.

Acknowledgments

This study was supported by grants from Chiayi Chang Gung Hospital, Taiwan (CMRPG6E0272, CMRPG6E0273).

Conflict of Interest

The authors declare no conflict of interest.

^* These authors contributed equally to this work.

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Correspondence

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