Skip to main content

Advertisement

SpringerLink
Log in

Genotoxicity of Psychotropic Drugs in Experimental and Clinical Studies

  • Published:
Neuroscience and Behavioral Physiology Aims and scope Submit manuscript

Data from studies of the genotoxic activity of psychotropic drugs published over the past 25 years were analyzed. Information describing the genotoxicity of psychotropic drugs was found to be fragmentary and inconsistent, and the experimental conditions in which they were produced often fail to meet accepted requirements. Among the 94 drugs considered, sufficient data for concluding that genotoxic properties are present or absent were found for only 9.6%. There is a need for a large-scale systematic reassessment of the genotoxicity of psychotropic drugs, especially first-generation drugs, based on modern methodology, including studies of mutagen-modifying activity. The desirability of monitoring the genotoxic status of patients treated with psychotropic drugs is emphasized, and this should contribute to an adequate assessment of the genotoxic risk of their use and determination of objective approaches to selecting drugs for safe therapy. The relevance of research to determine the role of primary DNA damage in the pathogenesis of mental illness is grounded.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Durnev, A. D., Zhanataev, A. K., Shreder, O. V., et al., “Genotype impairments and disease,” Molek. Med., 3, 3-19 (2013).

    Google Scholar 

  2. Houdhuri, S., Kaur, T., Jain, S., et al., “A review on genotoxicity in connection to infertility and cancer,” Chem. Biol. Interact., 345, 109531 (2021); https://doi.org/10.1016/j.cbi.2021.109531.

  3. Verdoux, H., Tournier, M., and Bégaud, B., “Antipsychotic prescribing trends: a review of pharmaco-epidemiological studies,” Acta Psychiatr. Scand., 121, No. 1, 4-10 (2010); https://doi.org/10.1111/j.1600-0447.2009.01425.x.

    Article  CAS  PubMed  Google Scholar 

  4. Verdoux, H., Tournier, M., and Bégaud, B., “Pharmacoepidemiology of psychotropic drugs: examples of current research challenges on major public health issues,” Epidemiol. Psichiatr. Soc., 18, No. 2, 107-113 (2009).

    Article  PubMed  Google Scholar 

  5. Patten, S. B., Waheed, W., and Bresee, L., “A review of pharmacoepidemiologic studies of antipsychotic use in children and adolescents,” Can. J. Psychiatry, 57, No. 12, 717-721 (2012); https://doi.org/10.1177/070674371205701202.

    Article  PubMed  Google Scholar 

  6. Filippova, L. M., Rapoport, N. A., Shapiro, Yu. L., and Aleksandrovskii, Yu. A., “Mutagenic activity of psychotropic drugs,” Genetika, 11, No. 6, 77-88 (1975).

    CAS  PubMed  Google Scholar 

  7. OECD Guidelines for the Testing of Chemicals, G. Section 4. Health Effects; https://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788.

  8. Steiblen, G., Benthem, J., and Johnson, G., “Strategies in genotoxicology: Acceptance of innovative scientific methods in a regulatory context and from an industrial perspective,” Mutat. Res. Genet. Toxicol. Environ. Mutagen., 853, 503171 (2020); https://doi.org/10.1016/j.mrgentox.2020.503171.

  9. National Library of Medicine. https://www.ncbi.nlm.nih.gov/PubMed (Accessed May 29, 2022).

  10. Scientific Electronic Library. https://elibrary.ru (Accessed May 29, 2022).

  11. Vidal Medicines Handbook. Anatomical-Therapeutic-Chemical (ATC) classification system [in Russian]. https://www.vidal.ru/drugs/atc (Accessed May 29, 2022).

  12. Vidal Medicines Handbook. Nosological Index [in Russian], https://www.vidal.ru/drugs/nosology (Accessed May 29, 2022).

  13. Mironov, A. N., Bunatyan, N. D., et al., Guidelines for Preclinical Drug Trials [in Russian], Grif i K., Moscow (2012), Part 1.

  14. Takasawa, H. Suzuki, H. and Ogawa, I., “Evaluation of a liver micronucleus assay in young rats (III): a study using nine hepatotoxicants by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)-Mammalian Mutagenicity Study Group (MMS),” Mutat. Res., 698, No. 1-2, 30-37 (2010); https://doi.org/10.1016/j.mrgentox.2010.02.009.

    Article  CAS  PubMed  Google Scholar 

  15. Asanami, S., Shimono, K., and Kaneda, S., “Transient hypothermia induces micronuclei in mice,” Mutat. Res., 413, No. 1, 7-14 (1998); https://doi.org/10.1016/s1383-5718(98)00004-7.

    Article  CAS  PubMed  Google Scholar 

  16. Guzmán, A., García, C., Marín, A. P., et al., “Formation of micronucleated erythrocytes in mouse bone-marrow under conditions of hypothermia is not associated with stimulation of erythropoiesis,” Mutat. Res., 656, No. 1-2, 8-13 (2008); https://doi.org/10.1016/j.mrgentox.2008.06.016.

    Article  CAS  PubMed  Google Scholar 

  17. Asanami, S. and Shimono, K., “Effects of chemically- and environmentally-induced hypothermia on micronucleus induction in rats,” Mutat. Res., 471, No. 1-2, 81-86 (2000); https://doi.org/10.1016/s1383-5718(00)00119-4.

    Article  CAS  PubMed  Google Scholar 

  18. Struwe, M., Greulich, K. O., Junker, U., et al., “Detection of photogenotoxicity in skin and eye in rat with the photo comet assay,” Photochem. Photobiol. Sci., 7, No. 2, 240-249 (2008); https://doi.org/10.1039/b715756h.

    Article  CAS  PubMed  Google Scholar 

  19. Agúndez, J. A. G., García-Martín, E., García-Lainez, G., Miranda, M. A., and Andreu, I., “Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS,” Sci. Rep., 10, No. 1, 6879 (2020); https://doi.org/10.1038/s41598-020-63651-y.

  20. Kersten, B., Zhang, J., Brendler-Schwaab, S. Y., Kasper, P., and Müller, L., “The application of the micronucleus test in Chinese hamster V79 cells to detect drug-induced photogenotoxicity,” Mutat. Res., 445, No. 1, 55-71 (1999); https://doi.org/10.1016/s1383-5718(99)00143-6.

    Article  CAS  PubMed  Google Scholar 

  21. Rao, K. P. and Rao, M. S., “Effects of fluphenazine hydrochloride on the bone-marrow cells of Swiss mice,” Mutat. Res., 89, No. 3, 237-240 (1981); https://doi.org/10.1016/0165-1218(81)90242-1.

    Article  CAS  PubMed  Google Scholar 

  22. Suryanarayana, A., Rita, P., and Reddy, P. P., “Cytogenetic effects of trifluoperazine in mice,” Food Chem. Toxicol., 25, No. 8, 615-617 (1987); https://doi.org/10.1016/0278-6915(87)90023-8.

    Article  CAS  PubMed  Google Scholar 

  23. Gasiorowski, K., Malinka, W., Swiatek P., and Jaszczyszyn, A., “Antimutagenic activity of new analogues of fluphenazine,” Cell. Mol. Biol. Lett., 8, No. 4, 927-942 (2003).

    CAS  PubMed  Google Scholar 

  24. Gasiorowski, K., Brokos, B., Kulma, A., Ogorzałek, A., and Skórkowska, K., “Impact of four antimutagens on apoptosis in genotoxically damaged lymphocytes in vitro,” Cell. Mol. Biol. Lett., and 6, No. 3, 649-675 (2001).

  25. Shoyab, M., “Enhancement by fluphenazine of dimethylbenz[a]-anthracene-induced mammary tumorigenesis in rats,” Cancer Lett., 18, No. 3, 297-303 (1983); https://doi.org/10.1016/0304-3835(83)90239-2.

    Article  CAS  PubMed  Google Scholar 

  26. Ahuja, Y. R., Jaju, M., and Saxena, R., “Cytogenetic effects of psychotropic drug haloperidol on human lymphocytes,” Arzneimittelforschung, 34, No. 6, 699-701 (1984).

    CAS  PubMed  Google Scholar 

  27. Kitchin, R. M., Walton, C. S., Martino, R. M., and Curry, P. T., “In vivo induction of sister chromatid exchange by clinical doses of haloperidol in Swiss albino mice,” Environ. Mol. Mutagen., 10, No. 4, 433-436 (1987); https://doi.org/10.1002/em.2850100412.

    Article  CAS  PubMed  Google Scholar 

  28. Smith, M., de Souza, M. A., Pugliese, S., and Mari, J. de J., “In vivo study of the mutagenicity of biperidine, pipotiazine, chlorpromazine, and haloperidol,” Am. J. Med. Genet., 67, No. 2, 238 (1996); https://doi.org/10.1002/ajmg.1320670206.

  29. Gajski, G., Gerić, M., and Garaj-Vrhovac, V., “Evaluation of the in vitro cytogenotoxicity profile of antipsychotic drug haloperidol using human peripheral blood lymphocytes,” Environ. Toxicol. Pharmacol., 38, No. 1, 316-324 (2014); https://doi.org/10.1016/j.etap.2014.06.011.

    Article  CAS  PubMed  Google Scholar 

  30. Asanami, S. and Shimono, K., “Species-level differences between mice and rats in regards to micronucleus induction with the hypothermia-inducing drug haloperidol,” Mutat. Res., 676, No. 1-2, 102-105 (2009); https://doi.org/10.1016/j.mrgentox.2009.04.011.

    Article  CAS  PubMed  Google Scholar 

  31. CPMP opinion following an article 36 referral Sertindole, https://www.ema.europa.eu/en/documents/referral/opinion-following-article-36-referral-sertindole-international-non-proprietary-name-inn-sertindole_en.pdf (Accessed May 29, 2022).

  32. Pharmacology review(s). Application number 200603, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200603Orig1s000PharmR.pdf (Accessed May 29, 2022).

  33. Kefelioğlu, H., Atlı Şekeroğlu, Z., Coşguner, G., et al., “Ziprasidone induces cytotoxicity and genotoxicity in human peripheral lymphocytes,” Drug Chem. Toxicol., 40, No. 4, 425-431 (2017); https://doi.org/10.1080/01480545.2016.1252920.

  34. Togar, B. Turkez, H. Tatar, A. et al., “The genotoxic potentials of some atypical antipsychotic drugs on human lymphocytes,” Toxicol. Ind. Health, 28, No. 4, 327-333 (2012); https://doi.org/10.1177/0748233711410919.

    Article  CAS  PubMed  Google Scholar 

  35. Asghari, M., Shaghaghi, Z., Farzipour, S., et al., “Radioprotective effect of olanzapine as an anti-psychotic drug against genotoxicity and apoptosis induced by ionizing radiation on human lymphocytes,” Mol. Biol. Rep., 46, No. 6, 5909-5917 (2019); https://doi.org/10.1007/s11033-019-05024-x.

    Article  CAS  PubMed  Google Scholar 

  36. Shokrzadeh, M., Mohammadpour, A., Modanloo, M., et al., “Cytotoxic effects of aripiprazole on mkn45 and nih3t3 cell lines and genotoxic effects on human peripheral blood lymphocytes,” Arq. Gastroenterol., 56, No. 2, 155-159 (2019); https://doi.org/10.1590/S0004-2803.201900000-31.

    Article  PubMed  Google Scholar 

  37. Picada, J. N., Dos Santos B. de, J., Celso, F., et al., “Neurobehavioral and genotoxic parameters of antipsychotic agent aripiprazole in mice,” Acta Pharmacol. Sin., 32, No. 10, 1225-1232 (2011); https://doi.org/10.1038/aps.2011.77.

  38. Pastor, N., Kaplan, C., Domínguez, I., et al., “Cytotoxicity and mitotic alterations induced by non-genotoxic lithium salts in CHO cells In vitro,” Toxicol. In Vitro, 23, No. 3, 432-438 (2009); https://doi.org/10.1016/j.tiv.2009.01.009.

    Article  CAS  PubMed  Google Scholar 

  39. Slamenová, D., Budayová, E., Gábelová, A., et al., “Results of genotoxicity testing of mazindol (degonan), lithium carbonicum (contemnol) and dropropizine (ditustat) in Chinese hamster V79 and human EUE cells,” Mutat. Res., 169, No. 3, 171-177 (1986); https://doi.org/10.1016/0165-1218(86)90096-0.

    Article  PubMed  Google Scholar 

  40. Invega, INN-paliperidone, https://www.ema.europa.eu/en/documents/scientific-discussion/invega-epar-scientific-discussion_en.pdf (Accessed May 29, 2022).

  41. Pharmacology review(s). Application number 22-264, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022264s000pharmr.pdf (Accessed May 29, 2022).

  42. Reagila, INN-cariprazine, https://www.ema.europa.eu/en/documents/assessment-report/reagila-epar-public-assessment-report_en.pdf (Accessed May 29, 2022).

  43. VRAYLARTM (cariprazine) capsules, https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204370lbl.pdf (Accessed May 29, 2022).

  44. Seredenin, S. B., Avrutskii, G. Y. A., Fatkhulin, I. A., et al., “Study of chromosome aberrations in the lymphocytes of patients treated with phenazepam and Sydnocarb,” Khim.-Farm. Zh., 14, 14-18 (1980).

    CAS  Google Scholar 

  45. Seredenin, S. B. and Durnev, A. D., “Studies of the mutagenicity of phenazepam and Sidnocarb,” Khim.-Farm. Zh., 19, No. 4, 395-399 (1985).

    CAS  Google Scholar 

  46. Durnev, A. D., Complex Studies of the Mutagenic Properties of Drugs Used Separately and in Combination [in Russian], Author's Abstract of Master's Thesis, Moscow (1982).

  47. Igarashi, M., Setoguchi, M., Takada, S., et al., “Optimum conditions for detecting hepatic micronuclei caused by numerical chromosome aberration inducers in mice,” Mutat. Res., 632, No. 1-2, 89-98 (2007); https://doi.org/10.1016/j.mrgentox.2007.04.012.

    Article  CAS  PubMed  Google Scholar 

  48. Leal Garza, C. H., Valenciano Cedillo, G. G., Rojas Alvarado, M. A., et al., “Mutagenic activity of diazepam evaluated by in vivo cytogenetic tests,” Arch. Med. Res., 29, No. 4, 285-289 (1998).

    CAS  PubMed  Google Scholar 

  49. Schuler, M., Gudi, R., Cheung, J., et al., “Evaluation of phenolphthalein, diazepam and quinacrine dihydrochloride in the in vitro mammalian cell micronucleus test in Chinese hamster ovary (CHO) and TK6 cells,” Mutat. Res., 702, No. 2, 219-229 (2010); https://doi.org/10.1016/j.mrgentox.2010.04.004.

    Article  CAS  PubMed  Google Scholar 

  50. Azab, M., Khabour, O. F., Alzoubi, K. H., et al., “Diazepam induced oxidative DNA damage in cultured human lymphocytes,” J. King Saud Univ. Sci., 30, No. 3, 412-416 (2018); https://doi.org/10.1016/j.jksus.2017.03.002.

    Article  Google Scholar 

  51. Ibrulj, S. and Duricić, E., “Genotoxicity of oxazepam-the micronucleus cytochalasin-B test,” Med. Arh., 56, No. 2, 61-64 (2002).

    PubMed  Google Scholar 

  52. Al-Terehi, M. N., Al-Saadi, M. A. K., Mugheer, A. H., et al., “Genotoxic effects of alprazolam in white albino rats,” Int. J. Biotechn. Allied Fields, 1, No. 6, 345-354 (2013).

    Google Scholar 

  53. Chłopkiewicz, B., Ejchart, A., and Anuszewska, E., “Tofisopam - evaluation of mutagenic and genotoxic properties,” Acta Pol. Pharm., 58, No. 1, 31-34 (2001).

    PubMed  Google Scholar 

  54. Rothfuss, A., O'Donovan, M., De Boeck, M., et al., “Collaborative study on fifteen compounds in the rat-liver Comet assay integrated into 2- and 4-week repeat-dose studies,” Mutat. Res., 702, No. 1, 40-69 (2010); https://doi.org/10.1016/j.mrgentox.2010.07.006.

    Article  CAS  PubMed  Google Scholar 

  55. Brambilla, G. and Martelli, A., “Update on genotoxicity and carcinogenicity testing of 472 marketed pharmaceuticals,” Mutat. Res., 681, No. 2-3, 209-229 (2009); https://doi.org/10.1016/j.mrrev.2008.09.002.

    Article  CAS  PubMed  Google Scholar 

  56. Giri, A. K. and Banerjee, S., “Genetic toxicology of four commonly used benzodiazepines: a review,” Mutat. Res., 340, No. 2-3, 93-108 (1996); https://doi.org/10.1016/s0165-1110(96)90042-1.

    Article  PubMed  Google Scholar 

  57. Carlo, P., Finollo, R., Ledda, A., et al., “Absence of liver DNA fragmentation in rats treated with high oral doses of 32 benzodiazepine drugs,” Fundam. Appl. Toxicol., 12, No. 1, 34-41 (1989); https://doi.org/10.1016/0272-0590(89)90059-6.

    Article  CAS  PubMed  Google Scholar 

  58. Susheela, M. and Rao, M. S., “Genotoxicity of chlordiazepoxide hydrochloride on the bone-marrow cells of Swiss mice,” Toxicol. Lett., 18, No. 1-2, 45-48 (1983); https://doi.org/10.1016/0378-4274(83)90069-3.

    Article  CAS  PubMed  Google Scholar 

  59. Stopper, H., Körber, C., Spencer, D. L., Kirchner, S., Caspary, W. J., and Schiffmann, D., “An investigation of micronucleus and mutation induction by oxazepam in mammalian cells,” Mutagenesis, 8, No. 5, 449-455 (1993); https://doi.org/10.1093/mutage/8.5.449.

    Article  CAS  PubMed  Google Scholar 

  60. Lafi, A. and Parry, J. M., “A study of the induction of aneuploidy and chromosome aberrations after diazepam, medazepam, midazolam and bromazepam treatment,” Mutagenesis, 3, No. 1, 23-27 (1988); https://doi.org/10.1093/mutage/3.1.23.

    Article  CAS  PubMed  Google Scholar 

  61. BuSpar® (buspirone, HCl USP), https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018731s051lbl.pdf (Accessed May 29, 2022).

  62. Zhanataev, A. K., Lisitsyna, T. A., and Durnev, A. D., et al, “Effectd of afobazole on DNA damage in patients with systemic lupus erythematosus,” Byull. Éksperim. Biol. Med., 148, No. 10, 404-407 (2009).

    Google Scholar 

  63. Zabrodina, A. K., Shreder, E. D., Shreder, O. V., et al., “Effect of afobazole and betaine on DNA damage in placental and embryonic tissues of rats with experimental streptozocin diabetes,” Bull. Exp. Biol. Med., 159, No. 6, 757-760 (2015); https://doi.org/10.1007/s10517-015-3068-5.

    Article  CAS  PubMed  Google Scholar 

  64. Shreder, E. D., Shreder, O. V., Zabrodina, V. V., et al., “Afobazole modifies the neurotoxic and genotoxic effects in rat prenatal alcoholization model,” Bull. Exp. Biol. Med., 157, No. 4, 492-495 (2014); https://doi.org/10.1007/s10517-014-2599-5.

    Article  CAS  PubMed  Google Scholar 

  65. Durnev, A. D., Zhanataev, A. K., and Eremina, N. V., Genetic Toxicology [in Russian], Mittel Press typography, Moscow (2022).

    Google Scholar 

  66. Almeida, I. V., Domingues, G., Soares, L. C., et al., “Evaluation of cytotoxicity and mutagenicity of the benzodiazepine flunitrazepam in vitro and in vivo,” Braz. J. Pharm. Sci., 50, No. 2, 251-256 (2014); https://doi.org/10.1590/S1984-82502014000200003.

    Article  CAS  Google Scholar 

  67. Imovane. Product Monograph, https://products.sanofi.ca/en/imovane.pdf (Accessed May 29, 2022).

  68. TovaltTM ODT (zolpidem tartrate), https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021412lbl.pdf (Accessed May 29, 2022).

  69. Stilnox CR (zolpidem tartrate). Australian Product information, https://apps.medicines.org.au/files/swpsticr.pdf (Accessed May 29, 2022).

  70. Zerene, INN-Zaleplon, https://www.ema.europa.eu/en/documents/scientific-discussion/zerene-epar-scientific-discussion_en.pdf (Accessed May 29, 2022).

  71. Precedex (dexmedetomidine hydrochloride) injection label, https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021038s021lbl.pdf (Accessed May 29, 2022).

  72. Sileo, dexmedetomidine hyrdochloride, https://www.ema.europa.eu/en/documents/assessment-report/sileo-epar-public-assessment-report_en.pdf (Accessed May 29, 2022).

  73. Belsombra (suvorexant) tablets, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204569s006lbl.pdf (Accessed May 29, 2022).

  74. Madrigal-Bujaidar, E., Madrigal-Santillán, E. O., Alvarez-Gonzalez, I., et al., “Micronuclei induced by imipramine and desipramine in mice: a subchronic study,” Basic Clin. Pharmacol. Toxicol., 103, No. 6, 569-573 (2008); https://doi.org/10.1111/j.1742-7843.2008.00328.x.

    Article  CAS  PubMed  Google Scholar 

  75. Saxena, R. and Ahuja, Y. R., “Genotoxicity evaluation of the tricyclic antidepressants amitriptyline and imipramine using human lymphocyte cultures,” Environ. Mol. Mutagen., 12, No. 4, 421-430 (1988); https://doi.org/10.1002/em.2860120410.

    Article  CAS  PubMed  Google Scholar 

  76. Madrigal-Bujaidar, E., Cárdenas García, Y. et al., “Chromosomal aberrations induced by imipramine and desipramine in mouse,” Hum. Exp. Toxicol., 29, No. 4, 297-302 (2010); https://doi.org/10.1177/0960327110361751.

    Article  CAS  PubMed  Google Scholar 

  77. Solek, P. Koszla, O. Mytych, J. et al., “Neuronal life or death linked to depression treatment: the interplay between drugs and their stress-related outcomes relate to single or combined drug therapies,” Apoptosis, 24, No. 9-10, 773-784 (2019); https://doi.org/10.1007/s10495-019-01557-5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. El-Fikya, S. A., Abou-ZaidbIbrahim, F. A., AlyFahmyc M. F. M., et al., “Genotoxic effect of the tricyclic antidepressant drug clomipramine hydrochloride in somatic and germ cells of male mice, Asian Pacific J. Trop. Dis., 6, No. 4, 321-327 (2016); https://doi.org/10.1016/S2222-1808(15)61038-6.

    Article  CAS  Google Scholar 

  79. Hassanane, M. S. Hafiz, N. Radwan W., et al.,, “Genotoxic evaluation for the tricyclic antidepressant drug, amitriptyline,” Drug Chem. Toxicol., 35, No. 4, 450-455 (2012); https://doi.org/10.3109/01480545.2011.642382.

  80. Düsman, E., Almeida, I. V., Mariucci, R. G., et al., “Cytotoxicity and mutagenicity of fluoxetine hydrochloride (Prozac), C. with or without vitamins A and, in plant and animal model systems,” Genet. Mol. Res., 13, No. 1, 578-589 (2014); https://doi.org/10.4238/2014.January.28.3.

    Article  CAS  PubMed  Google Scholar 

  81. Elmorsy, E. Al-Ghafari, A. Almutairi, F. M. et al., “Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations,” Toxicol. In Vitro, 44, 154-163 (2017); https://doi.org/10.1016/j.tiv.2017.07.011.

  82. Celexa Label, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020822s047lbl.pdf (Accessed May 29, 2022).

  83. Attia, S. M. and Bakheet, S. A., “Citalopram at the recommended human doses after long-term treatment is genotoxic for male germ cell,” Food Chem. Toxicol., 53, 281-285 (2013); https://doi.org/10.1016/j.fct.2012.11.051.

  84. Battal, D., Aktas, A., Sungur, M. A., et al., “In vivo genotoxicity assessment of sertraline by using alkaline comet assay and the cytokinesis-block micronucleus assay,” Basic Clin. Pharmacol. Toxicol., 113, No. 5, 339-346 (2013); https://doi.org/10.1111/bcpt.12095.

    Article  CAS  PubMed  Google Scholar 

  85. Istifli, E. S., Çelik, R., Hüsunet, M. T., et al., “In vitro cytogenotoxic evaluation of sertraline,” Interdiscip. Toxicol., 11, No. 3, 181-188 (2018); https://doi.org/10.2478/intox-2018-0015.

    Article  CAS  PubMed  Google Scholar 

  86. Label for Fluvoxamine maleate, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021519s009lbl.pdf (Accessed May 29, 2022).

  87. Cobanoglu, H., Coskun, M., Çayir, A., et al., “In vitro genotoxic and cytotoxic effects of doxepin and escitalopram on human peripheral lymphocytes,” Drug Chem. Toxicol., 41, No. 2, 238-244 (2018); https://doi.org/10.1080/01480545.2017.1365885.

  88. Avuloglu Yilmaz, E., Unal, F., and Yuzbasioglu, D., “Evaluation of cytogenetic and DNA damage induced by the antidepressant drug-active ingredients, trazodone and milnacipran, in vitro,” Drug Chem. Toxicol., 40, No. 1, 57-66 (2017); https://doi.org/10.1080/01480545.2016.1174870.

  89. Norizadeh Tazehkand, M. and Topaktas, M., “The in vitro genotoxic and cytotoxic effects of remeron on human peripheral blood lymphocytes,” Drug Chem. Toxicol., 38, No. 3, 266-271 (2015); https://doi.org/10.3109/01480545.2014.947425.

  90. Ayabaktı, S. and Yavuz Kocaman, A., “Cytogenotoxic effects of venlafaxine hydrochloride on cultured human peripheral blood lymphocytes,” Drug Chem. Toxicol., 43, No. 2, 192-199 (2020); https://doi.org/10.1080/01480545.2018.1486410.

  91. Hassani, M., Ghassemi-Barghi, N., Modanloo, M., et al., “Cytotoxic effects of duloxetine on MKN45 and NIH3T3 cell lines and genotoxic effects on human peripheral blood lymphocytes,” Arq. Gastroenterol., 56, No. 4, 372-376 (2019); https://doi.org/10.1590/S0004-2803.201900000-71.

    Article  PubMed  Google Scholar 

  92. Madrigal-Bujaidar, E., Álvarez-González, I., Madrigal-Santillán, E. O., et al., “Evaluation of duloxetine as micronuclei inducer in an acute and a subchronic assay in mouse,” Biol. Pharm. Bull., 38, No. 8, 1245-1249 (2015); https://doi.org/10.1248/bpb.b15-00152.

    Article  CAS  PubMed  Google Scholar 

  93. Pereira, P., Gianesini, J., da Silva Barbosa, C., et al., “Neurobehavioral and genotoxic parameters of duloxetine in mice using the inhibitory avoidance task and comet assay as experimental models,” Pharmacol. Res., 59, No. 1, 57-61 (2009); https://doi.org/10.1016/j.phrs.2008.09.014.

    Article  CAS  PubMed  Google Scholar 

  94. Bruhwyler, J. Liégeois, J. F. and Géczy, J., “Pirlindole: a selective reversible inhibitor of monoamine oxidase A. A review of its preclinical properties,” Pharmacol. Res., 36, No. 1, 23-33 (1997); https://doi.org/10.1006/phrs.1997.0196.

    Article  CAS  PubMed  Google Scholar 

  95. Valdoxan, INN-agomelatine, https://www.ema.europa.eu/en/documents/product-information/valdoxan-epar-product-information_en.pdf (Accessed May 29, 2022).

  96. Trintellix (vortioxetine) label, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204447s013lbl.pdf (Accessed May 29, 2022).

  97. Sovrima, INN-idebenone, https://www.ema.europa.eu/en/documents/assessment-report/sovrima-epar-public-assessment-report_en.pdf (Accessed May 29, 2022).

  98. Galal, A. F., Lamiaa, M. S., Mahrousa, M. H., Somaia, A. N., and Omar, M. E., “Citicoline ameliorates neuro- and genotoxicity induced by acute malathion intoxication in rats,” J. Biosci. Appl. Res., 5, No. 2, 246-261 (2019); https://doi.org/10.21608/jbaar.2019.146800.

  99. Shiwaku, and H. Okazawa, “Impaired DNA damage repair as a common feature of neurodegenerative diseases and psychiatric disorders,” Curr. Mol. Med., P. 15, No. 2, 119-128 (2015); https://doi.org/10.2174/1566524015666150303002556.

  100. 100 Czarny, H., Kwiatkowski, D., Toma, M., et al., “Impact of single nucleotide polymorphisms of base excision repair genes on DNA damage and efficiency of DNA repair in recurrent depression disorder,” Mol. Neurobiol., 54, No. 6, 4150-4159 (2017); https://doi.org/10.1007/s12035-016-9971-6.

    Article  CAS  PubMed  Google Scholar 

  101. Zhang, P., Dilley, C., and Mattson, M. P., “DNA damage responses in neural cells: Focus on the telomere,” Neuroscience, and 145, No. 4, 1439-1448 (2007); https://doi.org/10.1016/j.neuroscience.2006.11.052.

    Article  CAS  Google Scholar 

  102. Subba Rao, K., “Mechanisms of disease: DNA repair defects and neurological disease,” Nat. Clin. Pract. Neurol., 3, No. 3, 162-172 (2007); https://doi.org/10.1038/ncpneuro0448.

    Article  CAS  PubMed  Google Scholar 

  103. Raza, M. U., Tufan, T., Wang, Y., et al., “DNA Damage in Major Psychiatric Diseases,” Neurotox. Res., 30, No. 2, 251-267 (2016); https://doi.org/10.1007/s12640-016-9621-9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  104. Bonassi, S., El-Zein, R., Bolognesi, C., et al., “Micronuclei frequency in peripheral blood lymphocytes and cancer risk: evidence from human studies,” Mutagenesis, 26, No. 1, 93-100 (2011); https://doi.org/10.1093/mutage/geq075.

    Article  CAS  PubMed  Google Scholar 

  105. Fenech, M., Holland, N., Zeiger, E., et al., “The HUMN and HUMNxL international collaboration projects on human micronucleus assays in lymphocytes and buccal cells-past, present and future,” Mutagenesis, and 26, No. 1, 239-245 (2011); https://doi.org/10.1093/mutage/geq051.

    Article  CAS  Google Scholar 

  106. Collins, A. R., “The comet assay for DNA damage and repair: principles, applications, and limitations,” Mol. Biotechnol., 26, No. 3, 249-261 (2004); https://doi.org/10.1385/MB:26:3:249.

    Article  CAS  PubMed  Google Scholar 

  107. Muraleedharan, A., Menon, V., Rajkumar, R. P., et al., “Assessment of DNA damage and repair efficiency in drug naïve schizophrenia using comet assay,” J. Psychiatr. Res., 68, 47-53 (2015); https://doi.org/10.1016/j.jpsychires.2015.05.018.

  108. Topak, O. Z., Ozdel, O., Dodurga, Y., and Secme, M., “An evaluation of the differences in DNA damage in lymphocytes and repair efficiencies in patients with schizophrenia and schizoaffective disorder,” Schizophr. Res., 202, 99-105 (2018); https://doi.org/10.1016/j.schres.2018.06.052.

  109. Psimadas, D,. Messini-Nikolaki, N., Zafiropoulou, M., et al., “DNA damage and repair efficiency in lymphocytes from schizophrenic patients,” Cancer Lett., 204, No. 1, 33-40 (2004); https://doi.org/10.1016/j.canlet.2003.09.022.

    Article  CAS  PubMed  Google Scholar 

  110. Kalaev, V. N., Skamrova, G. B., and Ignatova, I. V., “Evaluation of the stability of the genetic material of men with paranoid schizophrenia at different stages of treatment using a micronucleus test in the buccal epithelium,” Ékol. Genetika, 13, No. 3, 3-14 (2015).

    Google Scholar 

  111. Kalaev, V. N., Nikitina, O. G., Nikitina, T. Yu., et al., “ Micronucleus test in the buccal epithelium of patients with schizophrenia at different stages of treatment of the disease,” Sistemn. Anal. Upravl. Biomed. Sist., 9, No. 4, 817-821 (2010).

  112. Andreazza, A. C., Frey, B. N., Erdtmann, B., et al., “DNA damage in bipolar disorder,” Psychiatry Res., 153, No. 1, 27-32 (2007); https://doi.org/10.1016/j.psychres.2006.03.025.

    Article  CAS  PubMed  Google Scholar 

  113. Frey, B. N., Andreazza, A. C., Kunz, M., et al., “Increased oxidative stress and DNA damage in bipolar disorder: a twin-case report,” Prog. Neuropsychopharmacol. Biol. Psychiatry, 31, No. 1, 283-285 (2007); https://doi.org/10.1016/j.pnpbp.2006.06.011.

    Article  CAS  PubMed  Google Scholar 

  114. Czarny, P. Kwiatkowski, D. Kacperska, D. et al., “Elevated level of DNA damage and impaired repair of oxidative DNA damage in patients with recurrent depressive disorder,” Med. Sci. Monit., 21, 412-418 (2015); https://doi.org/10.12659/MSM.892317.

  115. Rybka, J. Kędziora-Kornatowska, K. Banaś-Leżańska, P. et al., “Interplay between the pro-oxidant and antioxidant systems and proinflammatory cytokine levels, in relation to iron metabolism and the erythron in depression [published correction appears in Free Radic. Biol. Med., 197, 69 (2014)],” Free Radic. Biol. Med., 63, 187-194 (2013); https://doi.org/10.1016/j.freeradbiomed.2013.05.019.

  116. Ahmadimanesh, M. Abbaszadegan, M. R. Morshedi Rad D., et al., “Effects of selective serotonin reuptake inhibitors on DNA damage in patients with depression,” J. Psychopharmacol., 33, No. 11, 1364-1376 (2019); https://doi.org/10.1177/0269881119874461.

  117. Ng, F. Berk, M. Dean, O. et al., “Oxidative stress in psychiatric disorders: evidence base and therapeutic implications,” Int. J. Neuropsychopharmacol., 11, No. 6, 851-876 (2008); https://doi.org/10.1017/S1461145707008401.

    Article  CAS  PubMed  Google Scholar 

  118. Bozkurt, G. Abay, E. Ates, I. et al., “Clastogenicity of selective serotonin-reuptake inhibitors,” Mutat. Res., 558, No. 1-2, 137-144 (2004); https://doi.org/10.1016/j.mrgentox.2003.11.005.

    Article  CAS  PubMed  Google Scholar 

  119. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV, American Psychiatric Association, Washington DC (1994), 4th edition.

  120. Torres-Bugarín, O., Pacheco-Gutiérrez, A. G., Vázquez-Valls, E., et al., “Micronuclei and nuclear abnormalities in buccal mucosa cells in patients with anorexia and bulimia nervosa,” Mutagenesis, 29, No. 6, 427-431 (2014); https://doi.org/10.1093/mutage/geu044.

    Article  CAS  PubMed  Google Scholar 

  121. Andrianopoulos, C., Stephanou, G., and Demopoulos, N. A., “Genotoxicity of hydrochlorothiazide in cultured human lymphocytes. I. Evaluation of chromosome delay and chromosome breakage,” Environ. Mol. Mutagen., 47, No. 3, 169-178 (2006); https://doi.org/10.1002/em.20180.

    Article  CAS  PubMed  Google Scholar 

  122. Mondal, S. C., Tripathi, D. N., Vikram, A., Ramarao, P., and Jena, G. B., “Furosemide-induced genotoxicity and cytotoxicity in the hepatocytes, but weak genotoxicity in the bone marrow cells of mice,” Fundam. Clin. Pharmacol., 26, No. 3, 383-392 (2012); https://doi.org/10.1111/j.1472-8206.2011.00927.x.

    Article  CAS  PubMed  Google Scholar 

  123. Snyder, R. D. and Green, J. W., “A review of the genotoxicity of marketed pharmaceuticals,” Mutat. Res., 488, No. 2, 151-169 (2001); https://doi.org/10.1016/s1383-5742(01)00055-2.

    Article  CAS  PubMed  Google Scholar 

  124. Stoll, R. E., Blanchard, K. T., Stoltz, J. H., et al., “Phenolphthalein and bisacodyl: assessment of genotoxic and carcinogenic responses in heterozygous p53 (+/-) mice and Syrian hamster embryo (SHE) assay,” Toxicol. Sci., 90, No. 2, 440-450 (2006); https://doi.org/10.1093/toxsci/kfj081.

    Article  CAS  PubMed  Google Scholar 

  125. Tsutsui, T. Tamura, Y. Yagi E., et al., “Cell-transforming activity and genotoxicity of phenolphthalein in cultured Syrian hamster embryo cells,” Int. J. Cancer,. 73, No. 5, 697-701 (1997); https://doi.org/10.1002/(sici)1097-0215(19971127)73:5<697::aidijc14>.3.0.co;2-3.

    Article  CAS  PubMed  Google Scholar 

  126. Bigatti, M. P., Corona, D., and Munizza, C., “Increased sister chromatid exchange and chromosomal aberration frequencies in psychiatric patients receiving psychopharmacological therapy,” Mutat. Res., 413, No. 2, 169-175 (1998); https://doi.org/10.1016/s1383-5718(98)00028-x.

    Article  CAS  PubMed  Google Scholar 

  127. Zhanataev, A. K., Durnev, A. D., and Seredenin, S. B., “A comparative study of the antimutagenic activity of afobazole in various regimens,” Byull. Éksperim. Biol. Med., 130, No. 11, 539-542 (2000).

    Google Scholar 

  128. Shreder, A. K., Shreder, E. D., Durnev, A. D., et al, “ Coupling of genotoxic and teratogenic effects due to cyclophosphamide and their modification by afobazole,” Gigien. Sanitar., 5, 64-68 (2011).

    Google Scholar 

  129. Neznamov, G. G., Syunyakov, T. S., Zolotov, N. N., et al., “Therapeutic effects of the anxiolytics phenazepam and afobazole on plasma malonaldehyde content and the mental state of patients with anxiety disorders,” Psikhichesk. Rasstr. Obshch. Med., 2, 40-47 (2014).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Zakusov Research Institute of Pharmacology, Moscow, Russia

    A. D. Durnev, N. V. Eremina, A. K. Zhanataev & L. G. Kolik

Authors
  1. A. D. Durnev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. V. Eremina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. K. Zhanataev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. G. Kolik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. V. Eremina.

Additional information

Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 122, No. 10, pp. 7–16, October, 2022.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Durnev, A.D., Eremina, N.V., Zhanataev, A.K. et al. Genotoxicity of Psychotropic Drugs in Experimental and Clinical Studies. Neurosci Behav Physi 53, 776–785 (2023). https://doi.org/10.1007/s11055-023-01469-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11055-023-01469-7

Keywords

Search

Navigation