The influence of the selective serotonin reuptake inhibitors fluoxetine, sertraline and citalopram on the regeneration process

Authors

DOI:

https://doi.org/10.33448/rsd-v10i17.24319

Keywords:

Sertraline; Fluoxetine; Citalopram; Bone regeneration; Fracture healing.

Abstract

Although bone tissue regeneration is a well-defined process, complications inherent to the treatment of fractures are still observed, one of them being the participation of serotonin in bone formation and remodeling. This is a hormone responsible for the regulation of several physiological processes and is correlated with the etiology of depression, whose treatment is given, especially, through the use of selective serotonin reuptake inhibitors (SSRI), which are related to an increased risk of fracture and bone loss. Thus, the aim of this study was to analyze the action of Fluoxetine, Sertraline and Citalopram in the bone regeneration process. Thirty-five Wistar rats were used, in which bone defects of 2 to 3 mm in length were made in the fibula. The animals received Fluoxetine Hydrochloride 60 days before the fracture was made, and Sertraline Hydrochloride and Citalopram Hydrochloride 40 days before, and continued for another 30 days after the procedure. Control animals received saline solution. The results show that the bone defect regeneration process occurred more effectively in animals belonging to the control group, when compared to the other treated groups. The same data were observed regarding the serum alkaline phosphatase rate, statistically different when compared to animals treated with SSRIs. These data allow us to suggest that Fluoxetine, Sertraline and Citalopram seem to negatively interfere in the bone regeneration process, leading to a delay and non-complete consolidation of fractures with bone loss.

References

Abu Nada, L. (2017). The effect of selective serotonin reuptake inhibitors on bone healing and titanium implant osseointegration. EScholarship@McGill. https://escholarship.mcgill.ca/concern/theses/h702q874b

Abu Nada, L., Al Subaie, A., Mansour, A., Wu, X., Abdallah, M., Al‐Waeli, H., Ersheidat, A., Stone, L. S., Murshed, M., & Tamimi, F. (2018). The antidepressant drug, sertraline, hinders bone healing and osseointegration in rats’ tibiae. Journal of Clinical Periodontology, 45(12), 1485–1497. https://doi.org/10.1111/jcpe.13015

Atli, O., Baysal, M., Aydogan-Kilic, G., Kilic, V., Ucarcan, S., Karaduman, B., & Ilgin, S. (2017). Sertraline-induced reproductive toxicity in male rats: evaluation of possible underlying mechanisms. Asian Journal of Andrology, 19(6), 672. https://doi.org/10.4103/1008-682x.192637

Brandão, M. M. C. (2015) Influência do uso de fármacos anti-depressivos na colocação de implantes dentários. Cidade do Porto, 2015.

Cray, J. J., Weinberg, S. M., Parsons, T. E., Howie, R. N., Elsalanty, M., & Yu, J. C. (2014). Selective serotonin reuptake inhibitor exposure alters osteoblast gene expression and craniofacial development in mice. Birth Defects Research Part A: Clinical and Molecular Teratology, 100(12), 912–923. https://doi.org/10.1002/bdra.23323

Cuquetto, D. C., Mill, J. G., & Amaral, F. T. do. (2012). Influência do uso de fluoxetina sobre o tempo de corrida em esteira ergométrica em ratos não treinados. Revista Brasileira de Educação Física E Esporte, 26(3), 375–381. https://doi.org/10.1590/s1807-55092012000300003

Ducy, P. (2011). 5-HT and bone biology. Current Opinion in Pharmacology, 11(1), 34–38. https://doi.org/10.1016/j.coph.2011.01.007

Ducy, P., & Karsenty, G. (2010). The two faces of serotonin in bone biology. Journal of Cell Biology, 191(1), 7–13. https://doi.org/10.1083/jcb.201006123

Feighner, J. P., & Overø, K. (1999). Multicenter, Placebo-Controlled, Fixed-Dose Study of Citalopram in Moderate-to-Severe Depression. The Journal of Clinical Psychiatry, 60(12), 824–830. https://doi.org/10.4088/jcp.v60n1204

Fernandes, E. V., Ramos, S. de P., Estanislau, C., & Venancio, E. J. (2012). Efeitos comportamentais e imunológicos da fluoxetina em ratos submetidos ao nado forçado. Psicologia: Teoria E Pesquisa, 28(4), 409–415. https://doi.org/10.1590/s0102-37722012000400008

Fleck, M. P., Berlim, M. T., Lafer, B., Sougey, E. B., Porto, J. A. D., Brasil, M. A., Juruena, M. F., & Hetem, L. A. (2009). Revisão das diretrizes da Associação Médica Brasileira para o tratamento da depressão (Versão integral). Brazilian Journal of Psychiatry, 31, S7–S17. https://doi.org/10.1590/S1516-44462009000500003

Fleck, M. P., Berlim, M. T., Lafer, B., Sougey, E. B., Porto, J. A. D., Brasil, M. A., Juruena, M. F., & Hetem, L. A. (2009). Revisão das diretrizes da Associação Médica Brasileira para o tratamento da depressão (Versão integral). Brazilian Journal of Psychiatry, 31, S7–S17. https://doi.org/10.1590/S1516-44462009000500003

Fonseca, D. D. D. (2020). Efeitos da fluoxetina sobre a odontogênese e o desenvolvimento dos tecidos mineralizados dos dentes [Tese de doutorado].

Garlingo, LCM. Williams, JN, Li, Y., Valiya Kambrath, A., & Sankar, U. (2018). A geração de fraturas femorais fechadas em camundongos: um modelo para estudar a cura óssea. Jornal de experimentos visualizados: JoVE, (138), 58122. https://doi.org/10.3791/58122. CSS. Patologia. Universidade Federal de Pernambuco, 2006. (sd). [Tese de mestrado].

Gartner, L. P. Hiatt, J. L., & Al, E. (2007). Tratado de histologia em cores. Elsevier.

Gill, J. S., Jamwal, S., Kumar, P., & Deshmukh, R. (2017). Sertraline and venlafaxine improves motor performance and neurobehavioral deficit in quinolinic acid induced Huntington’s like symptoms in rats: Possible neurotransmitters modulation. Pharmacological Reports: PR, 69(2), 306–313. https://doi.org/10.1016/j.pharep.2016.11.008

Gonçalves, P. C. (2013) Efeitos do tratamento com cloridrato de fluoxetina na mandíbula da prole de ratas tratadas durante a gestação e lactação. (Dissertação de Mestrado). Universidade Federal de Pernambuco.

Henn, JD (2010). Bioquímica Do Tecido Ósseo 1. https://www.ufrgs.com.br/lacvet/restrito/pdf/osso_henn.pdf

Hodge, J. M., Wang, Y., Berk, M., Collier, F. M., Fernandes, T. J., Constable, M. J., Pasco, J. A., Dodd, S., Nicholson, G. C., Kennedy, R. L., & Williams, L. J. (2013). Selective Serotonin Reuptake Inhibitors Inhibit Human Osteoclast and Osteoblast Formation and Function. Biological Psychiatry, 74(1), 32–39. https://doi.org/10.1016/j.biopsych.2012.11.003

Howie, R. N., Herberg, S., Durham, E., Grey, Z., Bennfors, G., Elsalanty, M., LaRue, A. C., Hill, W. D., & Cray, J. J. (2018). Selective serotonin re-uptake inhibitor sertraline inhibits bone healing in a calvarial defect model. International Journal of Oral Science, 10(3), 25. https://doi.org/10.1038/s41368-018-0026-x

Isola, J. G. M. P., & Moraes, P. C. (2012). Estrutura e regeneração óssea - revisão de literatura. Revista científica eletrônica de Medicina Veterinária , 18.

Jaegger, IMS (2015, 21 de maio). Aspectos morfológicos e imunohistoquímico da dentinogênese e pulpogênese em prol de ratas tratadas com fluoxetina durante a gestação e lactação. Repositório. ufpe.br. https://repositorio.ufpe.br/handle/123456789/16252

Junqueira, LCU & Carneiro, J. (2013). Histologia Básica Texto e Atlas (12ed)

Li, I-Hsun., Shih, J.-H., Jhao, Y.-T., Chen, H.-C., Chiu, C.-H., Chen, C.-F., Huang, Y.-S., Shiue, C.-Y., & Ma, K.-H. (2019). Regulation of Noise-Induced Loss of Serotonin Transporters with Resveratrol in a Rat Model Using 4-[18F]-ADAM/Small-Animal Positron Emission Tomography. Molecules, 24(7), 1344. https://doi.org/10.3390/molecules24071344

Lirani, A. P. R. Estudo comparativo dos efeitos do ultra-som e do laser de baixa intensidade no reparo ósseo de tíbia de rato. https://doi.org/10.11606/d.82.2004.tde-04052004-091046

Matos, J. A. de B. (2011). Aspectos morfológicos do desenvolvimento do osso alveolar de filhotes de ratas tratadas com fluoxetina durante a gestação. Repositorio.ufpe.br. https://repositorio.ufpe.br/handle/123456789/8325

Mir, M., Pereira, M. A., Geonmonond, R. S., Oliveira, U. S., Araújo, T. H., & Rossi, W. C. (2013). Uso de hidroxiapatita nanométrica em enxertos na fíbula de ratos. Ciência et Praxis, 6(11), 21–24. https://revista.uemg.br/index.php/praxys/article/view/2116

Rapport, M. M., Green, A. A., & Page, I. H. (1948). Serum Vasoconstrictor (SEROTONIN). Journal of Biological Chemistry, 176(3), 1243–1251. https://doi.org/10.1016/s0021-9258(18)57137-4

Refsgaard, L. K., Haubro, K., Pickering, D. S., Stuart, S. A., Robinson, E. S. J., & Andreasen, J. T. (2016). Effects of sertraline, duloxetine, vortioxetine, and idazoxan in the rat affective bias test. Psychopharmacology, 233(21-22), 3763–3770. https://doi.org/10.1007/s00213-016-4407-6

Regueira, L. S. (2013). Efeitos da fluoxetina na periodontogênese: Análise histológica e histomorfométrica em ratos. Repositorio.ufpe.br. https://repositorio.ufpe.br/handle/123456789/13120

Richter, T., Paluch, Z., & Alusik, S. (2014). The non-antidepressant effects of citalopram: a clinician’s perspective. Neuro Endocrinology Letters, 35(1), 7–12. https://pubmed.ncbi.nlm.nih.gov/24625921/

Riksen, E. A., Stunes, A. K., Kalvik, A., Gustafsson, B. I., Snead, M. L., Syversen, U., Lyngstadaas, S. P., & Reseland, J. E. (2010). Serotonin and fluoxetine receptors are expressed in enamel organs and LS8 cells and modulate gene expression in LS8 cells. European Journal of Oral Sciences, 118(6), 566–573. https://doi.org/10.1111/j.1600-0722.2010.00778.x

Rossi Jr, W. C. (2002). Influência de uma membrana de colágeno associada a extrato etanólico de própolis na consolidação de fraturas com perda óssea (Disssertação de Doutorado). Universidade Estadual de Campinas.

Santiago, I. M. A., Regueira, L. S., Correia, P. G., Alcântara, R. J. B., Evêncio, J. N., & Baratella-Evêncio, L. (2013) Effects of The Use of Fluoxetine Hydrochloride on the Development of Mineralized Tissues in Rats: a Systematic Review. R bras ci Saúde 17(2):181-188.

Seibel, M. J., Robins, S. P., & Bilezikian, J. P. (2006). Dynamics of bone and cartilage metabolism: [principles and clinical applications]. Academic Press.

Silva, F. S. (2016). Hidroxiapatita carbonatada e plasma rico em plaquetas em enxertos ósseos (Dissertação de Mestrado). Universidade Federal de Alfenas.

Tarabar, A. F., Hoffman, R. S., & Nelson, L. S. (2008). Citalopram overdose: Late presentation of torsades de pointes (TdP) with cardiac arrest. Journal of Medical Toxicology, 4(2), 101–105. https://doi.org/10.1007/bf03160963

Telles-Correia, D., Guerreiro, D. F., Oliveira, S., & Figueira, M. L. (2007). Diferenças farmacodinâmicas e farmacocinéticas entre os SSRI: implicações na prática clínica [Differences between SSRI's pharmacokinetics and pharmacodinamics]. Acta medica portuguesa, 20(2), 167–174.

Vestergaard, P., Rejnmark, L., & Mosekilde, L. (2008). Selective Serotonin Reuptake Inhibitors and Other Antidepressants and Risk of Fracture. Calcified Tissue International, 82(2), 92–101. https://doi.org/10.1007/s00223-007-9099-9

Viera, A; Varotto P, V; Roim B, L; D'ottaviano R; & Antequera, R. (2018). O efeito dos inibidores seletivos da recaptação da serotonina no metabolismo ósseo e sua influência na odontologia. ImplantNews Perio. v3(4): 675-680.

Warden, S. J., Robling, A. G., Sanders, M. S., Bliziotes, M. M., & Turner, C. H. (2005). Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology, 146(2), 685–693. https://doi.org/10.1210/en.2004-1259

Williams, L. J., Berk, M., Hodge, J. M., Kotowicz, M. A., Stuart, A. L., Chandrasekaran, V., Cleminson, J., & Pasco, J. A. (2018). Selective Serotonin Reuptake Inhibitors (SSRIs) and Markers of Bone Turnover in Men. Calcified Tissue International, 103(2), 125–130. https://doi.org/10.1007/s00223-018-0398-0

Yadav, V. K., Oury, F., Suda, N., Liu, Z. W., Gao, X. B., Confavreux, C., Klemenhagen, K. C., Tanaka, K. F., Gingrich, J. A., Guo, X. E., Tecott, L. H., Mann, J. J., Hen, R., Horvath, T. L., & Karsenty, G. (2009). A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell, 138(5), 976–989. https://doi.org/10.1016/j.cell.2009.06.051

Yadav, V. K., Ryu, J.-H., Suda, N., Tanaka, K. F., Gingrich, J. A., Schütz, G., Glorieux, F. H., Chiang, C. Y., Zajac, J. D., Insogna, K. L., Mann, J. J., Hen, R., Ducy, P., & Karsenty, G. (2008). Lrp5 Controls Bone Formation by Inhibiting Serotonin Synthesis in the Duodenum. Cell, 135(5), 825–837. https://doi.org/10.1016/j.cell.2008.09.059

Yildirim, G., & Eralp, F. E. (2021). Effect of Antidepressants and its Orthodontic Implications. Essentials of Dentistry. https://doi.org/10.5152/essentdent.2021.21005

Published

21/12/2021

How to Cite

SIQUEIRA, L. da C. .; SOUZA, K. da C. .; LEITE, M. R. G. .; FERREIRA, Ítalo A. S. .; ANDRADE, A. L. D. L. de .; ESTEVES, A.; ROSSI JUNIOR, W. C. . The influence of the selective serotonin reuptake inhibitors fluoxetine, sertraline and citalopram on the regeneration process. Research, Society and Development, [S. l.], v. 10, n. 17, p. e96101724319, 2021. DOI: 10.33448/rsd-v10i17.24319. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/24319. Acesso em: 20 may. 2022.

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Section

Health Sciences