Invasive Cervical Cancer and Antidepressants

To our knowledge, no prior population-based study has been published wherein the primary aim was to evaluate whether an association between psychotropic drug prescription and cervical cancer exists. Herein we have conducted the first study that primarily aimed to determine the association between antidepressants use and risk of invasive cervical cancer in the general population. This is a population-based study utilizing Taiwan’s National Health Insurance Research Database. We identified 26,262 cases with invasive cervical cancer and 129,490 controls. We adopted the conditional logistic regression model as the statistical method and adjusted for potential confounding factors. The prescription of selective serotonin reuptake inhibitors (SSRIs) (adjusted OR1⁄4 0.93, 95% CI1⁄4 0.84–1.04), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin norepinephrine reuptake inhibitors (SNRIs), mirtazapine and bupropion, adjusting for cumulative dose, was not associated with an increased, or decreased, risk for invasive cervical cancer. An association between trazodone prescription and invasive cervical cancer was observed (adjusted OR1⁄4 1.22, 95% CI1⁄4 1.03–1.43). An association between the major classes of antidepressants and invasive cervical cancer was not observed herein. Our preliminary finding regarding a possible association between trazodone and cervical cancer requires replication. , Yena Lee, Roger MD, PhD, g Chen, MD, PhD diabetes mellitus, ICD-9-CM = International Classification of Diseases, 9th Revision, Clinical Modification, MAOIs = monoamine oxidase inhibitors, NaSSA = noradrenergic and specific serotonergic antidepressant, NDRI = norepinephrine dopamine reuptake inhibitor, NHI = National Health Insurance, NHIRD = National Health Insurance Research Database, OR = odds ratio, RR = relative risk, SARI = serotonin antagonist and reuptake inhibitor, SNRIs = serotonin norepinephrine reuptake inhibitors, SSRIs = selective serotonin reuptake inhibitors, STD = WHO = World Health Organization. INTRODUCTION A ntidepressants are prescribed widely to treat common and chronic disorders including but not limited to depressive disorders, anxiety disorders, pain disorder, smoking cessation, and alcohol use disorders. Total expenditures on the antidepressant acquisition per year are estimated at 1 to 2 billion in United States. The trajectory for antidepressant prescription in North America has been increasing steadily during the past 2 decades. For example, between 1981 and 2000, total prescriptions of antidepressants increased from 3.2 to 14.5 million in Canada. Moreover, it is also reported that 10% of adults in the United States are prescribed an antidepressant with a significant increase in the number of adults in recent years prescribed multiple antidepressants for a period of time >6 months. Frequently prescribed classes of antidepressants include the selective serotonin reuptake inhibitors (SSRIs), serotonin– norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). The effects of antidepressants on cancer growth had been investigated in previous experimental and epidemiological studies, and important mechanisms of the effects were hypothesized to be related to serotonin, damage to DNA, cell cycle modulation, and immune regulation. Some experimental studies reported that antidepressants could promote the growth of some cancers. For example, fluoxetine and amitriptyline were found to promote fibrosarcomas, melanomas, and mammary carcinogenesis in rodent models. Moreover, desipramine was reported to exacerbate experimental carcinogenesis in the rat colon. Notwithstanding the foregoing studies, there are other studies with results that are not directionally consistent with the notion that antidepressants are carcinogenic. For example, antidepressants were noted to be associated with decreased incidence of pituitary adenomas, ibroadenomas, and to exert inhibitory er, colorectal cancer, melanoma, lymphoma in animal models. www.md-journal.com | 1 According to the World Health Organization (WHO), cervical cancer is the second most common cancer in women living in less developed regions in the world in 2012. There have been reports of possible association between antidepressant exposure and cervical cancer. The notion that antidepressants could lower cervical cancer was supported by an in vitro study that reported the cytotoxic effect of fluoxetine on cervical cancer cells. A separate in vitro study reported that serotonin application to HeLa cells (Human cervical cancer cells) did not increase the cellular survival. To our knowledge, only one epidemiological study investigated the effect of antidepressants on cervical cancer in clinical populations with HIV. When included as an AIDS-related cancer, invasive cervical cancer was not associated with antidepressant use. In Taiwan, cervical cancer is the seventh most common cause of death from cancer in women in 2013. In the present study, we aimed to explore the associations between the use of antidepressants and diagnosis of invasive cervical cancer with control of potential confounding factors (eg, socio-demographic factors, comorbid mental disorders, and physical disorders utilizing a nationwide population-based registry dataset). METHODOLOGY The National Health Insurance (NHI) program has been conducted by the Taiwanese government since March 1, 1995. It has been determined that 99.5% (till December 2008) of Taiwanese residents are represented in the NHI program, providing for a unique, inclusive, cross-national perspective. The National Health Insurance Research Database (NHIRD) included details about ambulatory care, inpatient care, prescription data, medical procedures, and diagnostic coding data. The data of population we used in this study was derived from NHIRD between January 1, 1997, and December 31, 2008. We conducted a population-based nested case-control study to assess the association between antidepressant use and the incidence of invasive cervical cancer. The diagnosis of invasive cervical cancer was established using the diagnostic code from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM): 180, and traced to the Catastrophic Illness Claim Dataset to assure the accuracy of the cancer diagnosis. The date of invasive cervical cancer claim was defined as the index date. Each case with invasive cervical cancer was matched to 5 female controls using incidence density sampling at the time of the cancer case diagnosed as invasive cervical cancer. Each control was free of cancer before the index date and matched to each cancer case by year of birth. For the control group, the sampled date was assigned as the index date. To ensure the same exposure time between the matched control cases, the control subjects who were dead or discontinued insurance before the index date were excluded. We identified antidepressants (N06A) according to the Anatomical Therapeutic Chemical classification system and retrieve prescription data from NHI files. Antidepressants were divided into different classes according to their mechanism of action including TCAs (ie, amitriptyline, clomipramine, dothiepin, doxepin, imipramine, maprotiline, and melitracen), MAOIs (ie, moclobemide, clorgyline, tranylcypromine, isocarboxacid, phenelzine, and selegiline), SSRIs (ie, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), SNRIs (ie, duloxetine, venlafaxine), SARI (trazodone), NaSSA (mirtazaChan et al pine), and NDRI (bupropion). The statistical measure used in this study for the amount of TCAs, MAOIs, SSRIs, SNRIs, SARI, NaSSa, and NDRI 2 | www.md-journal.com exposure was defined daily dose (DDD) defined by WHO. The cumulative doses were divided into 4 exposure dose levels as below, equal to and greater than 28 DDD (328 DDD), equal to and greater than 84 DDD (384 DDD), equal to and greater than 168 DDD (3168 DDD), and equal to and greater than 336 DDD (3336 DDD). Under consideration to minimize protopathic effect, we excluded antidepressants exposure in the year directly before the index date. Sociodemographic variables including age at the index date, income, and residential area were retrieved from the NHI files. Potential confounding factors were comorbid mental disorders, comorbid physical disorders, procedures, and other medication use were recognized in outpatient and inpatient claim records before the index date. Comorbid mental disorders included depressive disorders, whereas comorbid physical disorders included type 2 diabetes mellitus (DM), HIV infection, and sexual transmitted diseases (STD). Smoking status was not recorded in NHI files; consequently, we used smoking-related diseases (eg, chronic obstructive pulmonary disease [COPD] and asthma) to proxy smoking status. Frequency of Pap smear was taken into consideration since more frequent use of Pap smear may result in a higher frequency of detection of cervical cancer. The use of aspirin was also controlled as a variable. Statistical Analysis Descriptive statistics of invasive cervical cancer cases and controls were presented in terms of their demographic characteristics, comorbid disorders, medical procedure, and other medication use. The conditional logistic regression model was used to evaluate the effect of antidepressant on invasive cervical cancer. To understand variable aspects that antidepressant may affect the incidence of invasive cervical cancer, we examined the association between risk of invasive cervical cancer and 7 classes of antidepressants. In each class of antidepressant class, the crude odds ratio (OR) and the adjusted OR were calculated in 4 cumulative dosages (328 DDD, 384 DDD, 3168 DDD, and 3336 DDD). Corrected odds ratio are calculated after adjusted by demographic data and all confounding factors including depressive disorders, type 2 DM, COPD, asthma, HIV infection, STD, aspirin, and Pap smear frequency. The statistical significance of associations was assessed by using P value <0.05 or a 95% confidence interval (CI). All of the analyses were performed using SAS version 9.2. Ethics Statement The study was approved by the Institutional Review Board of Chiayi Chang Gung Memorial Hospital. RESULTS We identified 26,262 cases with a diagnosis of invasive cervical cancer and 129,490 matched controls between 1997 and 2008. The mean age of diagnosis of invasive cervical cancer was 55.5 13.2 years old. Sociodemographic variables including age, income, and urbanization were presented in Table 1. After matched to the age of cancer cases, ages of controls recruited were similar to cancer cases. The distribution of income levels and urbanization status between cancer cases and controls showed significantly different (P< 0.001). Medicine Volume 94, Number 42, October 2015 The percentages of comorbid mental disorders, comorbid physical disorders, medical procedures, and other medication use were presented in Table 2. Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. TABLE 1. Demographic Data of Cases and Controls