Abstract
Major depressive disorder (MDD) etiology is still not completely understood, and many individuals resist the traditional treatments. Chronic exposure to stressful events can contribute to development and progression and be involved in biological changes underlying MDD. Among the biological mechanisms involved, inflammatory changes and oxidative balance are associated with MDD pathophysiology. Quetiapine, a second-generation antipsychotic, induces a better therapeutic response in individuals refractory to traditional treatments. The main objectives of this research were as follows: to evaluate the effect of chronic mild stress (CMS) on depressive-like behaviors, oxidative stress, and inflammation in adult rats; to evaluate the possible antidepressant, antioxidant, and anti-inflammatory effects of quetiapine. The animals were submitted to CMS protocols. At the end of the CMS, the animals were submitted to a chronic treatment for 14 days with the following drugs: quetiapine (20 mg/kg), imipramine (30 mg/kg), and escitalopram (10 mg/kg). At the end of the treatments, the animals were evaluated in the open field tests, anhedonia (splash test), and forced swimming. The animals were euthanized after the behavioral tests, and serum samples were collected. Myeloperoxidase (MPO) activity and interleukin-6 (IL-6) levels were analyzed. CMS induced an increase in depressive-like behaviors, and quetiapine significantly reduced these behaviors. MPO activity and IL-6 levels increased in the serum of animals submitted to CMS. Quetiapine significantly reduced MPO activity and IL-6 levels. These results corroborate other evidence, indicating that chronic stress is a relevant phenomenon in the etiology of depression and suggesting that quetiapine induces an antidepressant effect because it reduces oxidative and inflammatory mechanisms.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All data are available in the main text.
Abbreviations
- ANOVA:
-
Analysis of variance
- COBEA:
-
Brazilian College of Animal Experimentation
- CRP:
-
C-reactive protein
- CMS:
-
Chronic mild stress
- DNA:
-
Deoxyribonucleic acid
- CEUA:
-
Ethics Committee on the Use of Animals
- UFFS:
-
Federal University of Fronteira Sul
- HClO:
-
Hypochlorous acid
- HPA:
-
Hypothalamic-pituitary-adrenal
- IDO:
-
Indoleamine-2,3-dioxygenase
- IL-1β:
-
Interleukin 1 beta
- IL-6:
-
Interleukin 6
- MDD:
-
Major depressive disorder
- MPO:
-
Myeloperoxidase
- NMDA:
-
N-methyl-D-aspartate
- PFC:
-
Prefrontal cortex
- ROS:
-
Reactive oxygen species
- TNF-α:
-
Tumor necrosis factor-α
- WHO:
-
World Health Organization
References
Alexopoulos GS (2019) Mechanisms and treatment of late-life depression. Transl Psychiatry 9:188. https://doi.org/10.1038/s41398-019-0514-6
Almeida MS, Nunes MA, Camey S et al (2012) Transtornos mentais em uma amostra de gestantes da rede de atenção básica de saúde no Sul do Brasil. Cad Saúde Pública 28:385–394. https://doi.org/10.1590/S0102-311X2012000200017
Aronson S, Delgado P (2004) Escitalopram. Drugs Today 40:121. https://doi.org/10.1358/dot.2004.40.2.799424
Burstein O, Franko M, Gale E et al (2017) Escitalopram and NHT normalized stress-induced anhedonia and molecular neuroadaptations in a mouse model of depression. PLoS ONE 12:e0188043. https://doi.org/10.1371/journal.pone.0188043
Cantù F, Ciappolino V, Enrico P et al (2021) Augmentation with atypical antipsychotics for treatment-resistant depression. J Affect Disord 280:45–53. https://doi.org/10.1016/j.jad.2020.11.006
Che Y, Zhou Z, Shu Y et al (2015) Chronic unpredictable stress impairs endogenous antioxidant defense in rat brain. Neurosci Lett 584:208–213. https://doi.org/10.1016/j.neulet.2014.10.031
Chernoloz O, El Mansari M, Blier P (2012) Effects of sustained administration of quetiapine alone and in combination with a serotonin reuptake inhibitor on norepinephrine and serotonin transmission. Neuropsychopharmacol 37:1717–1728. https://doi.org/10.1038/npp.2012.18
Colasanto M, Madigan S, Korczak DJ (2020) Depression and inflammation among children and adolescents: a meta-analysis. J Affect Disord 277:940–948. https://doi.org/10.1016/j.jad.2020.09.025
Coplan JD, Gopinath S, Abdallah CG, Berry BR (2014) A neurobiological hypothesis of treatment-resistant depression - mechanisms for selective serotonin reuptake inhibitor non-efficacy. Front Behav Neurosci 8. https://doi.org/10.3389/fnbeh.2014.00189
Cross AJ, Widzowski D, Maciag C et al (2016) Quetiapine and its metabolite norquetiapine: translation from in vitro pharmacology to in vivo efficacy in rodent models: translational pharmacology of quetiapine. Br J Pharmacol 173:155–166. https://doi.org/10.1111/bph.13346
Ding Q, Li H, Tian X et al (2016) Zinc and imipramine reverse the depression-like behavior in mice induced by chronic restraint stress. J Affect Disord 197:100–106. https://doi.org/10.1016/j.jad.2016.03.017
Feng T, McEvoy JP, Miller BJ (2020) Longitudinal study of inflammatory markers and psychopathology in schizophrenia. Schizophr Res 224:58–66. https://doi.org/10.1016/j.schres.2020.10.003
Fernandes J, Gupta GL (2019) N-acetylcysteine attenuates neuroinflammation associated depressive behavior induced by chronic unpredictable mild stress in rat. Behav Brain Res 364:356–365. https://doi.org/10.1016/j.bbr.2019.02.025
Ferrari M, Godio M, Martini S et al (2022) Effect of quetiapine on inflammation and immunity: a systematic review. Int J Psychiatry Clin Pract 1–12. https://doi.org/10.1080/13651501.2022.2101928
Fiedorowicz JG, Cyranowski JM, Liu Z, Swartz HA (2019) Changes in inflammation with treatment for bipolar II depression: pilot trial data on differential effects of psychotherapy and medication. Neurol Psychiatry Brain Res 33:112–118. https://doi.org/10.1016/j.npbr.2019.07.007
Gałecki P, Florkowski A, Bobińska K et al (2010) Functional polymorphism of the myeloperoxidase gene (G-463A) in depressive patients. Acta Neuropsychiatr 22:218–222. https://doi.org/10.1111/j.1601-5215.2010.00483.x
Gamaro GD, Streck EL, Matté C et al (2003) Reduction of hippocampal Na+, K+-ATPase activity in rats subjected to an experimental model of depression. Neurochem Res 28:1339–1344. https://doi.org/10.1023/A:1024988113978
Garabadu D, Ahmad A, Krishnamurthy S (2015) Risperidone attenuates modified stress–re-stress paradigm-induced mitochondrial dysfunction and apoptosis in rats exhibiting post-traumatic stress disorder-like symptoms. J Mol Neurosci 56:299–312. https://doi.org/10.1007/s12031-015-0532-7
Garcia LSB, Comim CM, Valvassori SS et al (2009) Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats. Prog Neuropsychopharmacol Biol Psychiatry 33:450–455. https://doi.org/10.1016/j.pnpbp.2009.01.004
Gold PW, Machado-Vieira R, Pavlatou MG (2015) Clinical and biochemical manifestations of depression: relation to the neurobiology of stress. Neural Plast 2015:1–11. https://doi.org/10.1155/2015/581976
Halaris A, Meresh E, Fareed J et al (2012) 1. Interleukin-6 as a biomarker in major depressive disorder. Brain Behav Immun 26:S1. https://doi.org/10.1016/j.bbi.2012.07.025
Han J, Tian H, Lian Y et al (2015) Quetiapine mitigates the ethanol-induced oxidative stress in brain tissue, but not in the liver, of the rat. NDT 1473. https://doi.org/10.2147/NDT.S80505
Ignácio ZM, Réus GZ, Abelaira HM et al (2015) Acute and chronic treatments with quetiapine increase mitochondrial respiratory chain complex activity in the rat brain. Curr Neurovasc Res 12:283–292. https://doi.org/10.2174/1567202612666150603140912
Ignácio ZM, Réus GZ, Abelaira HM et al (2017a) Acute and chronic treatment with quetiapine induces antidepressant-like behavior and exerts antioxidant effects in the rat brain. Metab Brain Dis 32:1195–1208. https://doi.org/10.1007/s11011-017-0028-y
Ignácio ZM, Réus GZ, Abelaira HM et al (2017b) Quetiapine treatment reverses depressive-like behavior and reduces DNA methyltransferase activity induced by maternal deprivation. Behav Brain Res 320:225–232. https://doi.org/10.1016/j.bbr.2016.11.044
Ignácio ZM, Calixto AV, da Silva RH et al (2018) The use of quetiapine in the treatment of major depressive disorder: evidence from clinical and experimental studies. Neurosci Biobehav Rev 86:36–50. https://doi.org/10.1016/j.neubiorev.2017.12.012
Ignácio ZM, Réus GZ, Abelaira HM, Quevedo J (2014) Epigenetic and epistatic interactions between serotonin transporter and brain-derived neurotrophic factor genetic polymorphism: Insights in depression. Neuroscience 275:455–468. https://doi.org/10.1016/j.neuroscience.2014.06.036
Isingrini E, Camus V, Le Guisquet A-M et al (2010) Association between repeated unpredictable chronic mild stress (UCMS) procedures with a high fat diet: a model of fluoxetine resistance in mice. PLoS ONE 5:e10404. https://doi.org/10.1371/journal.pone.0010404
Kao Y-C, Ko C-Y, Wang S-C, Liu Y-P (2016) Protective effects of quetiapine on metabolic and inflammatory abnormalities in schizophrenic patients during exacerbated stage. Chin J Physiol 59:69–77. https://doi.org/10.4077/CJP.2016.BAE370
Kavoor AR (2020) COVID-19 in people with mental illness: challenges and vulnerabilities. Asian J Psychiatry 51:102051. https://doi.org/10.1016/j.ajp.2020.102051
Kilciksiz S, Demirel C, Erdal N et al (2008) The effect of N-acetylcysteine on biomarkers for radiation-induced oxidative damage in a rat model. Acta Med Okayama 62:403–9. https://doi.org/10.18926/AMO/30946
Kim H, Bang J, Chang HW et al (2012) Anti-inflammatory effect of quetiapine on collagen-induced arthritis of mouse. Eur J Pharmacol 678:55–60. https://doi.org/10.1016/j.ejphar.2011.12.017
Ko C-Y, Liu Y-P (2016) Disruptions of sensorimotor gating, cytokines, glycemia, monoamines, and genes in both sexes of rats reared in social isolation can be ameliorated by oral chronic quetiapine administration. Brain Behav Immun 51:119–130. https://doi.org/10.1016/j.bbi.2015.08.003
Kopschina Feltes P, Doorduin J, Klein HC et al (2017) Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy. J Psychopharmacol 31:1149–1165. https://doi.org/10.1177/0269881117711708
Lamers F, Milaneschi Y, Smit JH et al (2019) Longitudinal association between depression and inflammatory markers: results from the netherlands study of depression and anxiety. Biol Psychiat 85:829–837. https://doi.org/10.1016/j.biopsych.2018.12.020
Leonard BE (2018) Inflammation and depression: a causal or coincidental link to the pathophysiology? Acta Neuropsychiatr 30:1–16. https://doi.org/10.1017/neu.2016.69
Lindqvist D, Dhabhar FS, James SJ et al (2017) Oxidative stress, inflammation and treatment response in major depression. Psychoneuroendocrinology 76:197–205. https://doi.org/10.1016/j.psyneuen.2016.11.031
Liu S, Xu S, Wang Z et al (2018) Anti-depressant-like effect of sinomenine on chronic unpredictable mild stress-induced depression in a mouse model. Med Sci Monit 24:7646–7653. https://doi.org/10.12659/MSM.908422
Miller AH, Raison CL (2016) The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 16:22–34. https://doi.org/10.1038/nri.2015.5
National Research Council (US) Committee (2011) Guide for the care and use of laboratory animals. Washington (DC), National Academies Press (US)
Ng A, Tam WW, Zhang MW et al (2018) IL-1β, IL-6, TNF- α and CRP in elderly patients with depression or Alzheimer’s disease: systematic review and meta-analysis. Sci Rep 8:12050. https://doi.org/10.1038/s41598-018-30487-6
Nuñez NA, Joseph B, Pahwa M et al (2022) Augmentation strategies for treatment resistant major depression: a systematic review and network meta-analysis. J Affect Disord 302:385–400. https://doi.org/10.1016/j.jad.2021.12.134
Orsetti M, Canonico PL, Dellarole A et al (2007) Quetiapine prevents anhedonia induced by acute or chronic stress. Neuropsychopharmacol 32:1783–1790. https://doi.org/10.1038/sj.npp.1301291
Pan Y-J, Wang W-H, Huang T-Y et al (2018) Quetiapine ameliorates collagen-induced arthritis in mice via the suppression of the AKT and ERK signaling pathways. Inflamm Res 67:847–861. https://doi.org/10.1007/s00011-018-1176-1
Porsolt RD (2000) Animal models of depression: utility for transgenic research. Rev Neurosci 11. https://doi.org/10.1515/REVNEURO.2000.11.1.53
Ramirez K, Sheridan JF (2016) Antidepressant imipramine diminishes stress-induced inflammation in the periphery and central nervous system and related anxiety- and depressive-like behaviors. Brain Behav Immun 57:293–303. https://doi.org/10.1016/j.bbi.2016.05.008
Réus GZ, Abelaira HM, dos Santos MAB et al (2013) Ketamine and imipramine in the nucleus accumbens regulate histone deacetylation induced by maternal deprivation and are critical for associated behaviors. Behav Brain Res 256:451–456. https://doi.org/10.1016/j.bbr.2013.08.041
Rumble ME, White KH, Benca RM (2015) Sleep disturbances in mood disorders. Psychiatr Clin North Am 38:743–759. https://doi.org/10.1016/j.psc.2015.07.006
Sanchez C, Reines EH, Montgomery SA (2014) A comparative review of escitalopram, paroxetine, and sertraline: are they all alike? Int Clin Psychopharmacol 29:185–196. https://doi.org/10.1097/YIC.0000000000000023
Seo MK, Choi CM, McIntyre RS et al (2017) Effects of escitalopram and paroxetine on mTORC1 signaling in the rat hippocampus under chronic restraint stress. BMC Neurosci 18:39. https://doi.org/10.1186/s12868-017-0357-0
Seo MK, Lee JG, Park SW (2019) Effects of escitalopram and ibuprofen on a depression-like phenotype induced by chronic stress in rats. Neurosci Lett 696:168–173. https://doi.org/10.1016/j.neulet.2018.12.033
Shao Y, Peng H, Huang Q et al (2015) Quetiapine mitigates the neuroinflammation and oligodendrocyte loss in the brain of C57BL/6 mouse following cuprizone exposure for one week. Eur J Pharmacol 765:249–257. https://doi.org/10.1016/j.ejphar.2015.08.046
Snyder JS, Soumier A, Brewer M et al (2011) Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476:458–461. https://doi.org/10.1038/nature10287
Talarowska M, Kowalczyk M, Maes M et al (2020) Immune to happiness – inflammatory process indicators and depressive personality traits. Arch Med Sci 16:848–857. https://doi.org/10.5114/aoms.2019.83146
Talarowska M, Szemraj J, Gałecki P (2015) Myeloperoxidase gene expression and cognitive functions in depression. Adv Med Sci 60:1–5. https://doi.org/10.1016/j.advms.2014.06.001
Vaváková M, Ďuračková Z, Trebatická J (2015) Markers of oxidative stress and neuroprogression in depression disorder. Oxid Med Cell Longev 2015:1–12. https://doi.org/10.1155/2015/898393
Vos CF, Aarnoutse RE, Op de Coul MJM et al (2021) Tricyclic antidepressants for major depressive disorder: a comprehensive evaluation of current practice in the Netherlands. BMC Psychiatry 21:481. https://doi.org/10.1186/s12888-021-03490-x
Wang Y, Chang T, Chen Y-C et al (2013) Quetiapine add-on therapy improves the depressive behaviors and hippocampal neurogenesis in fluoxetine treatment resistant depressive rats. Behav Brain Res 253:206–211. https://doi.org/10.1016/j.bbr.2013.07.021
WHO - World Health Organization (2017) Depression and other common mental disorders global health estimates, Geneva. https://www.who.int/mental_health/management/depression/prevalence_global_health_estimates/en/. Accessed 17 Jan 2021
WHO - World Health Organization (2020) Depression: fact sheet. https://www.who.int/news-room/fact-sheets/detail/depression. Accessed 25 Fev 2021
Xuan Y, Yan G, Wu R et al (2015) The cuprizone-induced changes in 1H-MRS metabolites and oxidative parameters in C57BL/6 mouse brain: effects of quetiapine. Neurochem Int 90:185–192. https://doi.org/10.1016/j.neuint.2015.08.015
Young LM, Kheifets JB, Ballaron SJ, Young JM (1989) Edema and cell infiltration in the phorbol ester-treated mouse ear are temporally separate and can be differentially modulated by pharmacologic agents. Agents Actions 26:335–341. https://doi.org/10.1007/BF01967298
Zhang Y, Fan K, Liu Y, Liu G, Yang X, Ma J (2018) Cathepsin C aggravates neuroinflammation involved in disturbances of behaviour and neurochemistry in acute and chronic stress-induced murine model of depression. Neurochem Res 43(1):89–100. https://doi.org/10.1007/s11064-017-2320-y
Zhou Z, Zhen J, Karpowich NK et al (2007) LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science 317:1390–1393. https://doi.org/10.1126/science.1147614
Funding
This research was supported by grants from the Research and Innovation Support Foundation of Santa Catarina State (FAPESC) (ZMI), which made this research possible through the FAPESC/CNPq Public Call Notice No. 06/2016—Support for CTI Infrastructure for Young Researchers. Translational Psychiatry Laboratory (Brazil), Laboratory of Physiology Pharmacology and Psychopathology, and Laboratory of Cell Culture are funded by grants from the National Council for Scientific and Technological Development (CNPq) (MDB, ZMI, and GZR) and Research and Innovation Support Foundation of Santa Catarina State (FAPESC) (MDB, ZMI, and GZR), the University of Southern Santa Catarina (GZR), and the Federal University of Fronteira Sul (ZMI and MDB). MDB and GZR are 2 CNPq Research Fellows. JQ is a 1A CNPq Research Fellow.
Author information
Authors and Affiliations
Contributions
Roberta Eduarda Grolli: investigation, visualization, writing—original draft. Amanda Gollo Bertollo: investigation, writing—original Draft. João Paulo Behenck: investigation. Laura de Araujo Borba: investigation. Marcos Eduardo Plissari: investigation. Silvio José Batista Soares: investigation. Aline Manica: biochemical analyses. Larissa da Silva Joaquim: biochemical analyses. Fabricia Petronilho: biochemical analyses. João Quevedo: project administration. Margarete Dulce Bagatini: resources, biochemical analyses. Gislaine Zilli Réus: resources, writing—original draft. Zuleide Maria Ignácio: project administration, resources, funding acquisition, methodology.
Corresponding author
Ethics declarations
Ethics approval
All experimental procedures involving the use of animals were performed following the ethical principles governed by the Brazilian College of Animal Experimentation (COBEA) and after approval by the Federal University of Fronteira Sul (UFFS) Ethics Committee on the Use of Animals (CEUA-UFFS), protocol number 23205.004257/2017–96.
Competing interests
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.
About this article
Cite this article
Grolli, R.E., Bertollo, A.G., Behenck, J.P. et al. Quetiapine effect on depressive-like behaviors, oxidative balance, and inflammation in serum of rats submitted to chronic stress. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1423–1433 (2023). https://doi.org/10.1007/s00210-023-02406-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-023-02406-8