Citalopram at the recommended human doses after long-term treatment is genotoxic for male germ cell

Abstract

The present study was aimed to examine if multiple oral administration of citalopram, an antidepressant drug, has any genotoxic potential on germ cells of male mice. Mice were treated with citalopram for 4 or 8 weeks at the doses of 6, 12 and 24 mg/kg/day and were sacrificed 24 h after the last dose. Multiple exposures to 12 and 24 mg/kg/day citalopram significantly increased sperm DNA strand breaks (14.0 and 16.0, respectively, compared to the concurrent control of 6.8 at week 4 and 15.2 and 20.7, respectively, compared to the concurrent control of 7.2 at week 8) and aberrant primary spermatocytes (6.6% and 7.6%, respectively, compared to the control of 2.8% at week 4 and 7.4% and 8.4%, respectively, compared to the control of 3.2% at week 8) as well as oxidative DNA damage (2.7 and 3.1, respectively, compared to the control of 1.6 at week 4 and 3.3 and 3.9, respectively, compared to the control of 1.7 at week 8). Overall, this study provides that citalopram at the recommended human doses after long-term treatment is genotoxic for mouse germ cells. Thus, male patients receiving citalopram may stand at higher risk for abnormal reproductive outcomes, particularly in the reproductive ages.

Introduction

According to the National Institute of Mental Health (2009), depressive disorders afflict more than 6 million U.S. men annually. Antidepressant medications are the most common form of treatment, with almost 233 million prescriptions written in 2007 (IMS Health, 2008). Newer agents such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors with equivalent inhibitory action on serotonin reuptake have supplanted older treatment options because of the perceived favorable safety and side effects profiles associated with the newer antidepressants. Although the majority of antidepressants are prescribed for treatment of depression, they may also be used for treatment of anxiety disorders such as generalized anxiety disorder and obsessive–compulsive disorder. Antidepressant dispensing rates have continued to increase in recent years. Despite the rising use of antidepressants and the known effects of SSRIs on emission and ejaculation (Waldinger et al., 2001), few reports have evaluated the effect of antidepressants on male fertility or sperm quality (Hendrick et al., 2000).

In 2007, Tanrikut and Schlegel, reported two cases of men referred for male infertility evaluation who appeared to have antidepressant medication-associated changes in sperm concentration and motility (Tanrikut and Schlegel, 2007). Both men showed marked improvements in total motile sperm counts within a few weeks after discontinuation of antidepressant medication. This rapid recovery to normal semen parameters suggested that SSRIs affect sperm transport, not sperm production which would take months to recover. Given that SSRIs adversely affect emission and ejaculation, it is possible that they could negatively influence sperm transport, as well, with a resultant negative impact on sperm quality and number. An increase in sperm DNA fragmentation that occurs with delayed sperm transport has been observed in men with ejaculatory defects as well as men with obstructive azoospermia (Ramos et al., 2002). Attempts to assess sperm DNA integrity as determined by sperm DNA fragmentation indices have increasingly been incorporated as part of a male fertility evaluation, although clinical indications for these tests have yet to be defined (Collins et al., 2008). Importantly, DNA damage may exist independent of standard semen parameters (Saleh et al., 2002) and the degree of DNA fragmentation correlates with poorer fertility and pregnancy outcomes, even when techniques such as in vitro fertilization and intra-cytoplasmic sperm injection are applied (Evenson et al., 1999, Bungum et al., 2007).

Citalopram is one of the most widely used antidepressants. Apart from its antidepressant activity citalopram is also used for anxiety, panic disorders, obsessive–compulsive disorder and behavioral disturbances of dementia (Pollock, 2001). However, there is an increased concern about the possible adverse effects of citalopram on the reproductive and endocrine functions (Sloot et al., 2009). According to the OECD guidelines for genotoxicity testing, the drugs that are used widely or over a long duration of time need to be tested extensively for genotoxicity and other types of complication on the host system. Although information on the genotoxic effect of citalopram are scarce, other SSRI antidepressants in concentrations relevant to the treatment of human depression were found to promote fibrosarcomas, melanomas and mammary carcinogenesis in rodent models (Brandes et al., 1992, Hilakivi-Clarke et al., 1993). Moreover, the positive association among breast cancer risk and SSRIs users has been observed in some epidemiologic studies (Moorman et al., 2003, Steingart et al., 2003).

Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was also clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation (Brambilla et al., 2009). Citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis assay in rat liver.

Information on the germ cell toxicity of citalopram is limited and the molecular events leading to germ cell genotoxicity caused by multiple exposures to citalopram have not been investigated. Therefore, detail assessments of the genotoxicity of citalopram in germinal cell are warranted. Such assessments are essential since some of the effects produced by exposure to hazardous chemicals may be transmitted to next generation through gametes (Attia, 2008). In the current study, spermatocyte chromosomal analysis and sperm DNA damage at 4 and 8 weeks in animals exposed to multiple treatments with clinically relevant doses of citalopram were undertaken as markers of germ cell genotoxicity. In addition, spermiogram analysis after multiple exposures to citalopram for 8 weeks was performed to examine the effect of citalopram on the semen quality.