Evaluation of the hepatotoxic potential of citalopram in rats

Abstract

Background and Aims: Citalopram is a selective serotonin reuptake inhibitor with a high potency which is occasionally prescribed and used to treat major depression associated with mood disorders as a first-line drug. According to the results of previous studies, evidence of hepatotoxicity related to citalopram treatment were limited and conflicting. Therefore, we aimed to evaluate the hepatotoxicity potential of sub-chronic citalopram administration. Methods: Citalopram was administered to female rats orally in 5 and 10 mg/kg for 30 days. After the exposure period, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and direct bilirubin levels as biomarkers of hepatotoxicity were measured and histopathological examination of liver tissues was performed. Additionally, GSH levels of liver tissues were determined. Results: The risk of hepatotoxicity related to citalopram was shown by significant increases of serum hepatic biomarkers, AST, ALT, and total bilirubin in citalopram-administered groups. According to the histopathological findings, hepatocellular necrosis, hepatic nuclear asymmetry, and disarrangement of hepatic cord cells (hepatocytes) were prominent in the 10 mg/kg citalopram- administered group. On the other hand, there was no significant difference among the groups in terms of GSH levels. Conclusion: The results suggested that the administration of citalopram might cause hepatotoxic effects, depending on the dose.

Keywords

• Citalopram
• hepatotoxicity
• hepatic biomarker
• liver histology
• oxidative status

References

1. • Ahmadian, E., Eftekhari, A., Fard, J. K., Babaei, H., Nayebi, A. M., Mohammadnejad, D., & Eghbal, M. A. (2017). In vitro and in vivo evaluation of the mechanisms of citalopram-induced hepatotoxicity. Archives of Pharmacal Research, 40(11), 1296–1313.
2. • Alempijevic, T., Zec, S., & Milosavljevic, T. (2017). Drug-induced liver injury: Do we know everything? World Journal of Hepatology, 9(10), 491–502.
3. • Anderson, I. M., & Edwards, J. G. (2001). Guidelines for choice of selective serotonin reuptake inhibitor in depressive illness. Advances in Psychiatric Treatment, 7, 170–180.
4. • Babai, S., Auclert, L., & Le-Louët, H. (2018). Safety data and withdrawal of hepatotoxic drugs. Therapie. [Epub ahead of print] https://doi.org/10.1016/j.therap.2018.02.004
5. • Bech, P., Tanghøj, P., Andersen, H. F., & Overø, K. (2002). Citalopram dose-response revisited using an alternative psychometric approach to evaluate clinical effects of four fixed citalopram doses compared to placebo in patients with major depression. Psychopharmacology (Berl), 163(1), 20–25.
6. • Campion, S., Aubrecht, J., Boekelheide, K., Brewster, D. W., Vaidya, V. S., Anderson, L., Burt, D., Dere, E., Hwang, K., Pacheco, S., Saikumar, J., Schomaker, S., Sigman, M., & Goodsaid, F. (2013). The current status of biomarkers for predicting toxicity. Expert Opinion on Drug Metabolism & Toxicology, 9(11), 1391–408.
7. • Chen, M., Suzuki, A., Borlak, J., Andrade, R. J., & Lucena, M. I. (2015). Drug-induced liver injury: Interactions between drug properties and host factors. Journal of Hepatology, 63(2), 503–514.
8. • Church, R. J., & Watkins, P. B. (2017). The transformation in biomarker detection and management of drug-induced liver injury. Liver International, 37(11), 1582–1590.

9. • Dufour, D. R., Lott, J. A., Nolte, F. S., Gretch, D. R., Koff, R. S., & Seeff, L. B. (2000). Diagnosis and monitoring of hepatic injury. II. Recommendations for use of laboratory tests in screening, diagnosis, and monitoring. Clinical Chemistry, 46(12), 2050–2068.
10. • Ferguson, J. M. (2001). SSRI Antidepressant Medications: Adverse Effects and Tolerability. Primary Care Companion to the Journal of Clinical Psychiatry, 3(1), 22–27.
11. • Flores-Serrano, A., Vila-Luna, M., Álvarez-Cervera, F., Heredia- López, F., Góngora-Alfaro, J., & Pineda, J. C. (2013). Clinical doses of citalopram or reboxetine differentially modulate passive and active behaviors of female Wistar rats with high or low immobility time in the forced swimming test. Pharmacology Biochemistry & Behavior, 110, 89–97.
12. • Fredricson-Overo, K., & Svendsen, O. (1978). Hepatotoxicity of citalopram in rats and first-pass metabolism. Archives of Toxicology, 1, 177–180.
13. • Friedrich, M. E., Akimova, E., Huf, W., Konstantinidis, A., Papageorgiou, K., Winkler, D., Toto, S., Greil, W., Grohmann, R., & Kasper, S. (2016). Drug-Induced Liver Injury during Antidepressant Treatment: Results of AMSP, a Drug Surveillance Program. International Journal of Neuropsychopharmacology, 19(4).
14. • Gessel, L., & Alcorn, J. (2016). When Good Medications Go Bad, Don’t DILI Dally. Digestive Diseases and Sciences, 61(6), 1491–1494.
15. • Gowda, S., Desai, P. B., Hull, V. V., Math, A. A., Vernekar, S. N., & Kulkarni, S. S. (2009). A review on laboratory liver function tests. Pan African Medical Journal, 3, 17.
16. • Gwaltney-Brant, S. M. (2016). Nutraceuticals in Hepatic Diseases. In R.C. Gupta (Eds.), Nutraceuticals: Efficacy, Safety and Toxicity (pp. 7-99). London, UK: Academic Press.
17. • Herrlin, K., Yasui-Furukori, N., Tybring, G., Widén, J., Gustafsson, L. L., & Bertilsson, L. (2003). Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panel of healthy Swedes. British Journal of Clinical Pharmacology, 56(4), 415–421.
18. • Hunfeld, N. G. M., ten Berge, R. L., LeBrun, P. P. H., Smith, S. J., & Melief, P. H. G. J. (2010). Hepatotoxicity related to citalopram intake: a case report. International Journal of Risk & Safety in Medicine, 22, 1–5.
19. • Institutional Animal Care and Use Committee (IACUC) (2017). Anesthesia (Guideline). Retrieved from https://animal.research. uiowa.edu/iacuc-guidelines-anesthesia
20. • Jaeschke, H., Gores, G.J., Cederbaum, A. I., Hinson, J. A., Pessayre, D., & Lemasters J.J. (2002). Mechanisms of hepatotoxicity. Toxicological Sciences, 65(2), 166–176.
21. • Karlsson, L., Carlsson, B., Hiemke, C., Ahlner, J., Bengtsson, F., Schmitt, U., & Kugelberg, F. C. (2013). Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment. European Neuropsychopharmacology, 23(11), 1636–1644.
22. • Kim, E., & Nam, H. (2017). Prediction models for drug-induced hepatotoxicity by using weighted molecular fingerprints. BMC Bioinformatics, 18(7), 227.
23. • Kullak-Ublick, G. A., Andrade, R. J., Merz, M., End, P., Benesic, A., Gerbes, A. L., & Aithal, G. P. (2017). Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut, 66(6), 1154–1164.
24. • Lassila, T., Mattila, S., Turpeinen, M., & Tolonen, A. (2015). Glutathione trapping of reactive drug metabolites produced by biomimetic metalloporphyrin catalysts. Rapid Communications in Mass Spectrometry, 29(6), 521–532.
25. • Lassila, T., Rousu, T., Mattila, S., Chesné, C., Pelkonen, O., Turpeinen, M., & Tolonen, A. (2015). Formation of GSH-trapped reactive metabolites in human liver microsomes, S9 fraction, HepaRG-cells, and human hepatocytes. Journal of Pharmaceutical and Biomedical Analysis, 115, 345–351.
26. • Locher, C., Koechlin, H., Zion, S. R., Werner, C., Pine, D. S., Kirsch, I., Kessler, R. C., & Kossowsky, J. (2017). Efficacy and Safety of Selective Serotonin Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake Inhibitors, and Placebo for Common Psychiatric Disorders Among Children and Adolescents: A Systematic Review and Meta-analysis. JAMA Psychiatry, 74(10), 1011–1020.
27. • López-Torres, E., Lucena, M. I., Seoane, J., Verge, C., & Andrade, R. J. (2004). Hepatotoxicity related to citalopram (letter). American Journal of Psychiatry, 161(5), 923–924.
28. • Neumann, H., Csepregi, A., Evert, M., & Malfertheiner, P. (2008). Drug-induced liver disease related to citalopram (letter). Journal of Clinical Psychopharmacology, 28(2), 254–255.
29. • Ortega-Alonso, A., Stephens, C., Lucena, M. I., & Andrade, R. J. (2016). Case Characterization, Clinical Features and Risk Factors in Drug-Induced Liver Injury. International Journal of Molecular Sciences, 17(5).
30. • Raschi, E., & De Ponti, F. (2015). Drug- and herb-induced liver injury: Progress, current challenges and emerging signals of postmarketing risk. World Journal of Hepatology, 7(13), 1761–1771.
31. • Robles-Díaz, M., Medina-Caliz, I., Stephens, C., Andrade, R. J., & Lucena, M. I. (2016). Biomarkers in DILI: One More Step Forward. Frontiers in Pharmacology, 7, 267.
32. • Sanchez, C., Reines, E. H., & Montgomery, S. A. (2014). A comparative review of escitalopram, paroxetine, and sertraline: Are they all alike? International Clinical Psychopharmacology, 29(4), 185–196.
33. • Sangkuhl, K., Klein, T. E., & Altman, R. B. (2011). PharmGKB summary: citalopram pharmacokinetics pathway. Pharmacogenetics and Genomics, 21(11), 769–772.
34. • Sekar, S., Verhoye, M., Van Audekerke, J., Vanhoutte, G., Lowe, A. S., Blamire, A. M., Steckler, T., Van der Linden, A., & Shoaib, M. (2011). Neuroadaptive responses to citalopram in rats using pharmacological magnetic resonance imaging. Psychopharmacology, 213(2-3), 521–531.
35. • Sharbaf-Shoar, N., & Padhy, R. K. (Updated 20 January 2020). Citalopram. In: StatPearls [Internet]. Retrieved from https://www.ncbi. nlm.nih.gov/books/NBK482222/
36. • Singh, A., Bhat, T. K., & Sharma, O. P. (2011). Clinical Biochemistry of Hepatotoxicity. Journal of Clinical Toxicology, S:4.
37. • Solomons, K., Gooch, S., & Wong, A. (2005). Toxicity with selective serotonin reuptake inhibitors (letter). American Journal of Psychiatry, 162(6), 1225.
38. • Sturgill, M. G., & Lambert, G. H. (1997). Xenobiotic-induced hepatotoxicity: mechanisms of liver injury and methods of monitoring hepatic function. Clinical Chemistry, 43(8 Pt 2), 1512–1526.
39. • The National Institute for Health and Care Excellence (NICE) Pathways. (Updated 1 January, 2019). Depression in children and young people: identification and management. Retrieved from • https://www.nice.org.uk/guidance/ng134/documents/draftguideline
40. • The National Institute for Health and Care Excellence (NICE) Pathways. (Updated 10 September, 2020). Antidepressant treatment in adults. Retrieved from • https://pathways.nice.org.uk/pathways/depression/antidepressant- treatment-in-adults
41. • U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). (July 2005). Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. Retrieved from https://www.fda.gov/regulatoryinformation/ search-fda-guidance-documents/estimatingmaximum- safe-starting-dose-initial-clinical-trials-therapeutics- adult-healthy-volunteers
42. • Vega-Rivera, N. M., Gallardo-Tenorio, A., Fernández-Guasti, A., & Estrada-Camarena, E. (2016). The Post-Ovariectomy Interval Affects the Antidepressant-Like Action of Citalopram Combined with Ethynyl-Estradiol in the Forced Swim Test in Middle Aged Rats. Pharmaceuticals (Basel), 9(2).
43. • Vermoesen, K., Massie, A., Smolders, I., & Clinckers, R. (2012). The antidepressants citalopram and reboxetine reduce seizure frequency in rats with chronic epilepsy. Epilepsia, 53(5), 870–878.
44. • Voican, C. S., Corruble, E., Naveau, S., & Perlemuter, G. (2014). Antidepressant- induced liver injury: a review for clinicians. American Journal of Psychiatry, 171(4), 404–415.
45. • Whittington, C. J., Kendall, T., Fonagy, P., Cottrell, D., Cotgrove, A., & Boddington, E. (2004). Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet, 363(9418), 1341–1345.
46. • Wiese, B. (2011). Geriatric Depression: The Use of Antidepressants in The Elderly. British Columbia Medical Journal, 53(47), 341– 347.
47. • Zhang, J., Dennis, K. A., Darling, R. D., Alzghoul, L., Paul, I. A., Simpson, K. L., & Lin, R. C. (2013). Neonatal citalopram exposure decreases serotonergic fiber density in the olfactory bulb of male but not female adult rats. Frontiers in Cellular Neuroscience, 7, 67.