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Preclinical toxicological study of prolonged exposure to ketamine as an antidepressant

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Abstract

Background

Depression is one of the most common mentally debilitating diseases in the world. Ketamine has been recently identified as a potential novel antidepressant. Further animal model evaluations of the use of ketamine as an antidepressant are necessary to determine safety parameters for clinical use. Therefore, the objective of this study was to perform toxicological tests of prolonged treatment using three different doses of ketamine in adult male rats.

Methods

The animals were divided into four groups: three treated with 5, 10 or 20 mg/kg of ketamine and a control group treated with saline solution. Intraperitoneal route of treatment was administered daily for 3 weeks. Body weight, water and food intake were measured once a week, as well as evaluation of the functional observational battery, which includes methodic monitoring of motor activity, motor coordination, behavioral changes, and sensory/motor reflex responses. Upon completion of treatment period, all animals were euthanized by decapitation followed by immediate collection of samples, which included brain structures and blood for neurochemical, hematological and biochemical analyses.

Results

Rats treated with the highest tested dosage (20 mg/kg) of ketamine had lower weight gain in the 1st and 2nd weeks of treatment and all experimental groups had measurable alterations in the serotoninergic system.

Conclusions

Our data indicate that the alterations observed are minor and due to a predicted mechanism of action, which implies that ketamine is a promising drug for repurposing as an antidepressant.

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References

  1. Holubova K, Nekovarova T, Pistovcakova J, Sulcova A, Stuchlík A, Vales K. Pregnanolone glutamate, a novel use-dependent NMDA receptor inhibitor, exerts antidepressant-like properties in animal models. Front Behav Neurosci. 2014;8:1–10. https://doi.org/10.3389/fnbeh.2014.00130.

    Article  CAS  Google Scholar 

  2. World Health Organization. Depression and other common mental disorders: global health estimates. Geneva: World Health Organization; 2017.

    Google Scholar 

  3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington: American Psychiatric Publishing; 2013.

    Book  Google Scholar 

  4. Abdallah CG, Adams TG, Kelmendi B, Esterlis I, Sanacora G, Krystal JH. Ketamine’s mechanism of action: a path to rapid-acting antidepressants. Depress Anxiety. 2016;33:689–97. https://doi.org/10.1002/da.22501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zajecka JM. Clinical issues in long-term treatment with antidepressants. J Clin Psychiatry. 2000;61:20–5.

    PubMed  Google Scholar 

  6. Browne CA, Lucki I. Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol. 2013;4:1–18. https://doi.org/10.3389/fphar.2013.00161.

    Article  CAS  Google Scholar 

  7. Drewniany E, Han J, Hancock C, Jones RL, Lim J, Gorgani NN, et al. Rapid onset antidepressant action of ketamine: potential revolution in understanding and future pharmacologic treatment of depression. J Clin Pharm Ther. 2015;40:125–30. https://doi.org/10.1111/jcpt.12238.

    Article  CAS  PubMed  Google Scholar 

  8. Landrigan J, Shawaf F, Dwyer Z, Abizaid A, Hayley S. Interactive effects of ghrelin and ketamine on forced swim performance: implications for novel antidepressant strategies. Neurosci Lett. 2018;669:55–8. https://doi.org/10.1016/j.neulet.2016.08.015.

    Article  CAS  PubMed  Google Scholar 

  9. Garcia LSB, Comim CM, Valvassori SS, Réus GZ, Andreazza AC, Stertz L, et al. Chronic administration of ketamine elicits antidepressant-like effects in rats without affecting hippocampal brain-derived neurotrophic factor protein levels. Basic Clin Pharmacol Toxicol. 2008;103:502–6. https://doi.org/10.1111/j.1742-7843.2008.00210.x.

    Article  CAS  PubMed  Google Scholar 

  10. Van Calker D, Serchov T, Normann C, Biber K. Recent insights into antidepressant therapy: distinct pathways and potential common mechanisms in the treatment of depressive syndromes. Neurosci Biobehav Rev. 2018;88:63–72. https://doi.org/10.1016/j.neubiorev.2018.03.014.

    Article  CAS  PubMed  Google Scholar 

  11. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–4. https://doi.org/10.1016/S0006-3223(99)00230-9.

    Article  CAS  PubMed  Google Scholar 

  12. Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry. 2004;9:984–97. https://doi.org/10.1038/sj.mp.4001551.

    Article  CAS  PubMed  Google Scholar 

  13. Potter DE, Choudhury M. Ketamine: repurposing and redefining a multifaceted drug. Drug Discov Today. 2014;19:1848–54. https://doi.org/10.1016/j.drudis.2014.08.017.

    Article  CAS  PubMed  Google Scholar 

  14. Yilmaz A, Schulz D, Aksoy A, Canbeyli R. Prolonged effect of an anesthetic dose of ketamine on behavioral despair. Pharmacol Biochem Behav. 2002;71:341–4. https://doi.org/10.1016/S0091-3057(01)00693-1.

    Article  CAS  PubMed  Google Scholar 

  15. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64. https://doi.org/10.1001/archpsyc.63.8.856.

    Article  CAS  PubMed  Google Scholar 

  16. Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63:349–52. https://doi.org/10.1016/j.biopsych.2007.05.028.

    Article  CAS  PubMed  Google Scholar 

  17. Irwin SA, Iglewicz A, Nelesen RA, Lo JY, Carr CH, Romero SD, et al. Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept trial. J Palliat Med. 2013;16:958–65. https://doi.org/10.1089/jpm.2012.0617.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Xu Y, Li Y, Huang X, Chen D, She B, Ma D. Single bolus low-dose of ketamine does not prevent postpartum depression: a randomized, double-blind, placebo-controlled, prospective clinical trial. Arch Gynecol Obstet. 2017;295:1167–74. https://doi.org/10.1007/s00404-017-4334-8.

    Article  CAS  PubMed  Google Scholar 

  19. United States Environmental Protection Agency. Health effects test guidelines: neurotoxicity screening battery. Washington: US EPA; 1998.

    Google Scholar 

  20. Strasburger SE, Bhimani PM, Kaabe JH, Krysiak JT, Nanchanatt DL, Nguyen TN, et al. What is the mechanism of Ketamine’s rapid-onset antidepressant effect? A concise overview of the surprisingly large number of possibilities. J Clin Pharm Ther. 2017;42:147–54. https://doi.org/10.1111/jcpt.12497.

    Article  CAS  PubMed  Google Scholar 

  21. Cora MC, Kooistra L, Travlos G. Vaginal cytology of the laboratory rat and mouse: review and criteria for the staging of the estrous cycle using stained vaginal smears. Toxicol Pathol. 2015;43:776–93. https://doi.org/10.1177/0192623315570339.

    Article  CAS  PubMed  Google Scholar 

  22. Domonkos E, Borbélyová V, Csongová M, Bosý M, Kačmárová M, Ostatníková D, et al. Sex differences and sex hormones in anxiety-like behavior of aging rats. Horm Behav. 2017;93:159–65. https://doi.org/10.1016/j.yhbeh.2017.05.019.

    Article  CAS  PubMed  Google Scholar 

  23. McDougall SA, Park GI, Ramirez GI, Gomez V, Adame BC, Crawford CA. Sex-dependent changes in ketamine-induced locomotor activity and ketamine pharmacokinetics in preweanling, adolescent, and adult rats. Eur Neuropsychopharmacol. 2019;29:740–55. https://doi.org/10.1016/j.euroneuro.2019.03.013.

    Article  CAS  PubMed  Google Scholar 

  24. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–98. https://doi.org/10.1038/nature17998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Parise EM, Alcantara LF, Warren BL, Wright KN, Hadad R, Sial OK, et al. Repeated ketamine exposure induces an enduring resilient phenotype in adolescent and adult rats. Biol Psychiatry. 2013;74:750–9. https://doi.org/10.1016/j.biopsych.2013.04.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tizabi Y, Bhatti BH, Manaye KF, Das JR, Akinfiresoye L. Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar–Kyoto rats. Neuroscience. 2012;213:72–80. https://doi.org/10.1016/j.neuroscience.2012.03.052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jiang Y, Wang Y, Sun X, Lian B, Sun H, Wang G, et al. Short-and long-term antidepressant effects of ketamine in a rat chronic unpredictable stress model. Brain Behav. 2017;7:1–11. https://doi.org/10.1002/brb3.749.

    Article  Google Scholar 

  28. Martin LL, Smith DJ. Ketamine inhibits serotonin synthesis and metabolism in vivo. Neuropharmacology. 1982;21:119–25.

    Article  CAS  Google Scholar 

  29. Yamakura T, Petrenko AB, Baba Y, Sakimura K. Elucidation of anesthetic and analgesic effects of ketamine using NMDA receptor epsilon 1 subunit-deficient mice. Masui. 2006;55:S141–4.

    PubMed  Google Scholar 

  30. Nishimura M, Sato K, Okada T, Yoshiya I, Schloss P, Shimada S, et al. Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells. Anesthesiology. 1998;88:768–74.

    Article  CAS  Google Scholar 

  31. White KL, Roth BL. Psychotomimetic effects of kappa opioid receptor agonists. Biol Psychiatry. 2012;72:797–8. https://doi.org/10.1016/j.biopsych.2012.08.014.

    Article  CAS  PubMed  Google Scholar 

  32. Li L, Vlisides PE. Ketamine: 50 years of modulating the mind. Front Hum Neurosci. 2016;10:1–15. https://doi.org/10.3389/fnhum.2016.00612.

    Article  CAS  Google Scholar 

  33. Arterburn D, Sofer T, Boudreau DM, Bogart A, Westbrook EO, Theis MK, et al. Long-Term weight change after initiating second-generation antidepressants. J Clin Med. 2016;5:1–13. https://doi.org/10.3390/jcm5040048.

    Article  CAS  Google Scholar 

  34. European Agency for the Evaluation of Medicinal Products. Committee for veterinary medicinal products: ketamine summary report. London: EMEA; 1997.

    Google Scholar 

  35. Gauvin DV, Yoder JD, Holdsworth DL, Harter ML, May JR, Cotey N, et al. The standardized functional observational battery: its intrinsic value remains in the instrument of measure: the rat. J Pharmacol Toxicol Methods. 2016;82:90–108. https://doi.org/10.1016/j.vascn.2016.08.001.

    Article  CAS  PubMed  Google Scholar 

  36. Mathiasen JR, Moser VC. The Irwin test and functional observational battery (fob) for assessing the effects of compounds on behavior, physiology, and safety pharmacology in rodents. Curr Protoc Pharmacol. 2018;83:1–18. https://doi.org/10.1002/cpph.43.

    Article  Google Scholar 

  37. Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17:2921–7.

    Article  CAS  Google Scholar 

  38. Abdallah CG, Jackowski A, Salas R, Gupta S, Sato JR, Mao X, et al. The nucleus accumbens and ketamine treatment in major depressive disorder. Neuropsychopharmacology. 2017;42:1739–46. https://doi.org/10.1038/npp.2017.49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Abdallah CG, Sanacora G, Duman RS, Krystal JH. The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation? Pharmacol Ther. 2018;190:148–58. https://doi.org/10.1016/j.pharmthera.2018.05.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Grieco SF, Velmeshev D, Magistri M, Eldar-Finkelman H, Faghihi MA, Jope RS, et al. Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3. World J Biol Psychiatry. 2017;18:445–56. https://doi.org/10.1080/15622975.2016.1224927.

    Article  PubMed  Google Scholar 

  41. Viana GSB, Xavier CC, Vale EM, Lopes MJP, Alves VJ, Costa RO, et al. The monoaminergic pathways and inhibition of monoamine transporters interfere with the antidepressive-like behavior of ketamine. IBRO. 2018;4:7–13. https://doi.org/10.1016/j.ibror.2017.11.001.

    Article  Google Scholar 

  42. Martin DC, Introna RP, Aronstam RS. Inhibition of neuronal 5-HT uptake by ketamine, but not halothane, involves disruption of substrate recognition by the transporter. Neurosci Lett. 1990;112:99–103. https://doi.org/10.1016/0304-3940(90)90329-8.

    Article  CAS  PubMed  Google Scholar 

  43. Zhao Y, Sun L. Antidepressants modulate the in vitro inhibitory effects of propofol and ketamine on norepinephrine and serotonin transporter function. J Clin Neurosci. 2008;15:1264–9. https://doi.org/10.1016/j.jocn.2007.11.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yamamoto S, Ohba H, Nishiyama S, Harada N, Kakiuchi T, Tsukada H, et al. Subanesthetic doses of ketamine transiently decrease serotonin transporter activity: a PET study in conscious monkeys. Neuropsychopharmacology. 2013;38:2666–74. https://doi.org/10.1038/npp.2013.176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mukinda JT, Syce JA. Acute and chronic toxicity of the aqueous extract of Artemisia afra in rodents. J Ethnopharmacol. 2007;112:138–44. https://doi.org/10.1016/j.jep.2007.02.011.

    Article  CAS  PubMed  Google Scholar 

  46. Liang J, Chen SX, Huang S, Wu YY, Zhou CJ, Jiang DX, et al. Evaluation of toxicity studies of flavonoid fraction of Lithocarpus polystachyus Rehd in rodents. Regul Toxicol Pharmacol. 2017;88:283–90. https://doi.org/10.1016/j.yrtph.2017.07.006.

    Article  CAS  PubMed  Google Scholar 

  47. Chang T, Glazko AJ. Biotransformation and disposition of ketamine. Int Anesthesiol Clin. 1974;12:157–77.

    Article  CAS  Google Scholar 

  48. Dahan A, Olofsen E, Sigtermans M, Noppers I, Niesters M, Aarts L, et al. Population pharmacokinetic-pharmacodynamic modeling of ketamine-induced pain relief of chronic pain. Eur J Pain. 2011;15:258–67. https://doi.org/10.1016/j.ejpain.2010.06.016.

    Article  CAS  PubMed  Google Scholar 

  49. Zaccarelli-Magalhães J, Moreira N, Sandini TM, de Abreu GR, Sánchez-Sarmiento AM, Ricci EL, et al. Evaluation of prolonged exposure to varenicline in adult rats: haematological, biochemical and anatomopathological studies. Basic Clin Pharmacol Toxicol. 2018;122:305–9. https://doi.org/10.1111/bcpt.12913.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) [Grant Number: 305500/2013-9] and FAPESP (São Paulo Research Foundation) [Grant Number: 2018/05397-0]. This work is part of the first author’s Ph.D. thesis on the Graduate Program of Experimental and Compared Pathology, Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo.

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Authors and Affiliations

  1. Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva, 87, São Paulo, 05508-270, Brazil

    Julia Zaccarelli-Magalhães, André Rinaldi Fukushima, Natalia Moreira, Marianna Manes, Gabriel Ramos de Abreu & Helenice de Souza Spinosa

  2. Health Science Institute, Presbiterian Mackenzie University, Rua Da Consolação, 930, São Paulo, 01302-907, Brazil

    Esther Lopes Ricci

  3. School of Health Science IGESP, Rua da Consolação, 1025, São Paulo, 01301-000, Brazil

    Esther Lopes Ricci

  4. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, 3200 S. University Drive, Fort Lauderdale, FL, 33328, USA

    Paula A. Faria Waziry

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  1. Julia Zaccarelli-Magalhães
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  3. Natalia Moreira
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Correspondence to Julia Zaccarelli-Magalhães.

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Miss Zaccarelli-Magalhães reports grants from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), grants from CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), grants from FAPESP (São Paulo Research Foundation), during the conduct of the study.

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Zaccarelli-Magalhães, J., Fukushima, A.R., Moreira, N. et al. Preclinical toxicological study of prolonged exposure to ketamine as an antidepressant. Pharmacol. Rep 72, 24–35 (2020). https://doi.org/10.1007/s43440-019-00014-z

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