Etiopathogenesis of depression and experimental depression models used in preclinical studies

Abstract

Depression is the most frequent psychiatric illness among mood disorders, affecting approximately 10% of adults. Especially recurrent and moderate/severe depression can become a serious public health problem by impairing people’s life quality. The monoamine hypothesis is the most widely accepted hypothesis for clarifying the pathophysiology of depression. Depression’s pathogenesis and etiology, however, are still poorly understood. Tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin or noradrenaline reuptake inhibitors, different atypical antidepressants, and electroconvulsive therapy are currently available therapies for depression. Although these treatment options are effective, a large number of patients do not respond to treatment or do not attain long-term remission. Furthermore, present antidepressants used in clinics have disadvantages such as delayed onset of effects, side effects, and patient compliance problems. Therefore, the discovery of new antidepressant medications is crucial. Animal models are critical in investigating the etiology of depression and developing novel treatments. Hence, in this review, the main mechanisms involved in the etiopathogenesis of depression and the experimental depression models used in preclinical studies have been demonstrated.

Keywords

• Antidepressant
• depression
• depressive behavior
• etiopathogenesis
• experimental depression models

References

1. Borsini A, Zunszain PA. Advances in stem cells biology: new approaches to understand depression. In: Pfaff D, Christen Y, eds. Stem Cells in Neuroendocrinology. Cham (CH): Springer; (2016); 123-133. http://doi.org/10.1007/978-3-319-41603-8_10
2. Özkartal C and Arıcıoğlu F. Experimental models of depression: an overview to validity and reliability criteria. J Lab Anim. (2017); 1(2):95-104.
3. Lépine JP, Briley M. The increasing burden of depression. Neuropsychiatr Dis Treat. (2011); 7(Suppl 1):3-7. https://doi.org/10.2147/NDT.S19617
4. Power C, Reene E. and Lawlor BA. Depression in late life. Etiology, presentation, and management. Mental health and illness of the elderly mental health and illness worldwide, Singapur: Springer, (2017); 187-218.
5. Liu Q, He H, Yang J, Feng X, Zhao F, Lyu J. Changes in the global burden of depression from 1990 to 2017: Findings from the Global Burden of Disease study. J Psychiatr Res. (2020); 126:134-140. https://doi.org/10.1016/j.jpsychires.2019.08.002
6. McCarter T. Depression overview. Am Health Drug Benefits. (2008); 1(3):44-51.
7. Özder A and Kayalı Y. Depression. J. Fam. Med-Special Topics, (2018); 9(3):173-178.
8. Jesulola E, Micalos P, Baguley IJ. Understanding the pathophysiology of depression: From monoamines to the neurogenesis hypothesis model - are we there yet?. Behav Brain Res. (2018); 341:79-90. https://doi.org/10.1016/j.bbr.2017.12.025

9. National Institute of Mental Health, Depression (2021). https://www.nimh.nih.gov/health/topics/depression (Erişim Tarihi: 28.11.2021)
10. Becker M, Pinhasov A, Ornoy A. Animal models of depression: what can they teach us about the human disease?. Diagnostics (Basel). (2021); 11(1):123. Published 2021 Jan 14. https://doi.org/10.3390/diagnostics11010123
11. Boku S, Nakagawa S, Toda H, Hishimoto A. Neural basis of major depressive disorder: beyond monoamine hypothesis. Psychiatry Clin Neurosci. (2018); 72(1):3-12. https://doi.org/10.1111/pcn.12604
12. Liu Q, Li B, Zhu HY, Wang YQ, Yu J, Wu GC. Clomipramine treatment reversed the glial pathology in a chronic unpredictable stress-induced rat model of depression. Eur Neuropsychopharmacol. (2009); 19(11):796-805. https://doi.org/10.1016/j.euroneuro.2009.06.010
13. Gupta A, Sharma PK, Garg VK, Singh AK, Mondal SC. Role of serotonin in seasonal affective disorder. Eur Rev Med Pharmacol Sci. (2013); 17(1):49-55.
14. Bhatt S, Devadoss T, Manjula SN, Rajangam J. 5-HT3 receptor antagonism a potential therapeutic approach for the treatment of depression and other disorders. Curr Neuropharmacol. 2021; 19(9):1545-1559. https://doi.org/10.2174/1570159X18666201015155816
15. Saveanu RV, Nemeroff CB. Etiology of depression: genetic and environmental factors. Psychiatr Clin North Am. (2012); 35(1):51-71. https://doi.org/10.1016/j.psc.2011.12.001
16. Uğuz Ş and Yurdagül E. Noradrenerjik sistem ve depresyon. Klinik Psikiyatri Dergisi, (2002); 5(4):19-23.
17. Helvacı Çelik F and Hocaoğlu Ç. Major depressive disorder definition, etiology and epidemiology: a review J. Contemp. Med. (2016); 6(1):51-66. https://doi.org/10.16899/ctd.03180.
18. Maletic V, Eramo A, Gwin K, Offord SJ, Duffy RA. The role of norepinephrine and its α-adrenergic receptors in the pathophysiology and treatment of major depressive disorder and schizophrenia: a systematic review. Front Psychiatry. (2017);8:42. Published 2017 Mar 17. https://doi.org/10.3389/fpsyt.2017.00042
19. Brunello N, Mendlewicz J, Kasper S, et al. The role of noradrenaline and selective noradrenaline reuptake inhibition in depression. Eur Neuropsychopharmacol. (2002); 12(5):461-475. https://doi.org/10.1016/s0924-977x(02)00057-3
20. Liu Y, Zhao J, Guo W. Emotional Roles of mono-aminergic neurotransmitters in major depressive disorder and anxiety disorders. Front Psychol. (2018); 9:2201. Published 2018 Nov 21. https://doi.org/10.3389/fpsyg.2018.02201
21. Kulkarni SK and Dhir A. Current investigational drugs for major depression. Expert Opin Investig Drugs. (2009); 18(6):767-788. https://doi.org/10.1517/13543780902880850
22. Leggio GM, Salomone S, Bucolo C, et al. Dopamine D(3) receptor as a new pharmacological target for the treatment of depression. Eur J Pharmacol. (2013); 719(1-3):25-33. https://doi.org/10.1016/j.ejphar.2013.07.022
23. Dunlop BW and Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry. (2007); 64(3):327-337. https://doi.org/10.1001/archpsyc.64.3.327
24. Dailly E, Chenu F, Renard CE, Bourin M. Dopamine, depression and antidepressants. Fundam Clin Pharmacol. (2004); 18(6):601-607. https://doi.org/10.1111/j.1472-8206.2004.00287.x
25. Kendell SF, Krystal JH, Sanacora G. GABA and glutamate systems as therapeutic targets in depression and mood disorders. Expert Opin Ther Targets. (2005); 9(1):153-168. https://doi.org/10.1517/14728222.9.1.153
26. Tunnicliff G and Malatynska E. Central GABAergic systems and depressive illness. Neurochem Res. (2003); 28(6):965-976. https://doi.org/10.1023/a:1023287729363
27. Luscher B, Fuchs T. GABAergic control of depression-related brain states. Adv Pharmacol. (2015); 73:97-144. https://doi.org/10.1016/bs.apha.2014.11.003
28. Duman RS, Sanacora G, Krystal JH. Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments. Neuron. (2019); 102(1):75-90. https://doi.org/10.1016/j.neuron.2019.03.013
29. Prévot T, Sibille E. Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders. Mol Psychiatry. (2021); 26(1):151-167. https://doi.org/10.1038/s41380-020-0727-3
30. Özdemir O and Özdemir PG. Glutamatergic System and Schizophrenia. Current Approaches in Psychiatry, (2016); 8(4):394-405.
31. Del Río J and Frechilla D. Glutamate and depression. Schmidt WJ, Reith MEA. (Eds), Dopamine and glutamate in psychiatric disorders (2005). (p. 215-234). Totowa: Humana Press.
32. Kotan VO, Eker SS, Sivrioglu EY, Akkaya C. N-Methyl D-Aspartic Acid (NMDA) Receptors and depression. Current Approaches in Psychiatry, (2009); 1(1):36.
33. Corriger A, Pickering G. Ketamine and depression: a narrative review. Drug Des Devel Ther. (2019); 13:3051-3067. Published 2019 Aug 27. https://doi.org/10.2147/DDDT.S221437
34. Kadriu B, Musazzi L, Henter ID, Graves M, Popoli M, Zarate CA Jr. Glutamatergic Neurotransmission: pathway to developing novel rapid-acting antidepressant treatments. Int J Neuropsychopharmacol. (2019); 22(2):119-135. https://doi.org/10.1093/ijnp/pyy094
35. Iqbal SZ, Mathew SJ. Ketamine for depression clinical issues. Adv Pharmacol. (2020); 89:131-162. https://doi.org/10.1016/bs.apha.2020.02.005
36. Jelen LA and Stone JM. Ketamine for depression. Int Rev Psychiatry. (2021); n33(3):207-228. https://doi.org/10.1080/09540261.2020.1854194
37. Akdemir A, Örsel S, Karaoğlan A. Depresyon etiyolojisinde nöropeptidler. J Clin Psy. (2002); 5(4):24-29.
38. Rana T, Behl T, Sehgal A, et al. Exploring the role of neuropeptides in depression and anxiety. Prog Neuropsychopharmacol Biol Psychiatry. (2022); 114:110478. https://doi.org/10.1016/j.pnpbp.2021.110478
39. Werner FM and Coveñas R. Classical neurotransmitters and neuropeptides involved in major depression: a review. Int J Neurosci. (2010); 120(7):455-470. https://doi.org/10.3109/00207454.2010.483651
40. Xiao N and Le QT. Neurotrophic factors and their potential applications in tissue regeneration. Arch Immunol Ther Exp (Warsz). (2016); 64(2):89-99. https://doi.org/10.1007/s00005-015-0376-4
41. Castrén E, Võikar V, Rantamäki T. Role of neurotrophic factors in depression. Curr Opin Pharmacol. (2007); 7(1):18-21. https://doi.org/10.1016/j.coph.2006.08.009
42. Gümrü S and Aricioglu F. Neurotrophic factors and depression: pathophysiology and beyond. Clinical and Experimental Health Sciences, (2012); 2(2):53.
43. Phillips C. Brain-Derived neurotrophic factor, depression, and physical activity: making the neuroplastic connection. Neural Plast. (2017); 2017:7260130. https://doi.org/10.1155/2017/7260130
44. Castrén E, Monteggia LM. Brain-derived neurotrophic factor signaling in depression and antidepressant action. Biol Psychiatry. (2021); 90(2):128-136. https://doi.org/10.1016/j.biopsych.2021.05.008
45. Duman RS ama Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. (2006); 59(12):1116-1127. https://doi.org/10.1016/j.biopsych.2006.02.013
46. Masi G, Brovedani P. The hippocampus, neurotrophic factors and depression: possible implications for the pharmacotherapy of depression. CNS Drugs. (2011); 25(11):913-931. https://doi.org/10.2165/11595900-000000000-00000
47. Otsuki K, Uchida S, Hobara T, Yamagata H, Watanabe Y. Nihon Shinkei Seishin Yakurigaku Zasshi. (2012); 32(4):181-186.
48. Mayer SE, Lopez-Duran NL, Sen S, Abelson JL. Chronic stress, hair cortisol and depression: a prospective and longitudinal study of medical internship. Psychoneuroendocrinology. (2018); 92:57-65. https://doi.org/10.1016/j.psyneuen.2018.03.020
49. Dean J and Keshavan M. The neurobiology of depression: An integrated view. Asian J Psychiatr. (2017); 27:101-111. https://doi.org/10.1016/j.ajp.2017.01.025
50. Alfarez DN, Wiegert O, Joëls M, Krugers HJ. Corticosterone and stress reduce synaptic potentiation in mouse hippocampal slices with mild stimulation. Neuroscience. (2002); 115(4):1119-1126. https://doi.org/10.1016/s0306-4522(02)00483-9
51. Cerqueira JJ, Pêgo JM, Taipa R, Bessa JM, Almeida OF, Sousa N. Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors. J Neurosci. (2005); 25(34):7792-7800. https://doi.org/10.1523/JNEUROSCI.1598-05.2005
52. Ye Z, Kappelmann N, Moser S, et al. Role of inflammation in depression and anxiety: tests for disorder specificity, linearity and potential causality of association in the UK Biobank. EClinicalMedicine. (2021); 38:100992. https://doi.org/10.1016/j.eclinm.2021.100992
53. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. (2009); 65(9):732-741. https://doi.org/10.1016/j.biopsych.2008.11.029
54. Shadrina M, Bondarenko EA, Slominsky PA. Genetics factors in major depression disease. Front Psychiatry. (2018); 9:334. Published 2018 Jul 23. https://doi.org/10.3389/fpsyt.2018.00334
55. Kendall KM, Van Assche E, Andlauer TFM, Choi KW, Luykx JJ, Schulte EC, Lu Y. The genetic basis of major depression. Psychol Med. (2021); 51(13):2217-2230. https://doi.org/10.1017/S0033291721000441
56. Hasler G. Pathophysiology of depression: do we have any solid evidence of interest to clinicians?. World Psychiatry. (2010); 9(3):155-161. https://doi.org/10.1002/j.2051-5545.2010.tb00298.x
57. Planchez B, Surget A, Belzung C. Animal models of major depression: drawbacks and challenges. J Neural Transm (Vienna). (2019); 126(11):1383-1408. https://doi.org/10.1007/s00702-019-02084-y
58. Belzung C and Lemoine M. Criteria of validity for animal models of psychiatric disorders: focus on anxiety disorders and depression. Biol Mood Anxiety Disord. (2011); 1(1):9. Published 2011 Nov 7. https://doi.org/10.1186/2045-5380-1-9
59. Neumann ID, Wegener G, Homberg JR, et al. Animal models of depression and anxiety: What do they tell us about human condition?. Prog Neuropsychopharmacol Biol Psychiatry. (2011); 35(6):1357-1375. https://doi.org/10.1016/j.pnpbp.2010.11.028
60. Valvassori SS, Budni J, Varela RB, Quevedo J. Contributions of animal models to the study of mood disorders. Braz J Psychiatry. (2013); 35(29:121-131. https://doi.org/10.1590/1516-4446-2013-1168
61. Herzog DP, Beckmann H, Lieb K, Ryu S, Müller MB. Understanding and predicting antidepressant response: using animal models to move toward precision psychiatry. Front Psychiatry. (2018); 9:512. Published 2018 Oct 22. https://doi.org/10.3389/fpsyt.2018.00512
62. Wang Q, Timberlake MA 2nd, Prall K, Dwivedi Y. The recent progress in animal models of depression. Prog Neuropsychopharmacol Biol Psychiatry. (2017); 77:99-109. https://doi.org/10.1016/j.pnpbp.2017.04.008
63. Seligman ME, Maier SF. Failure to escape traumatic shock. J Exp Psychol. (1967); 74(1):1-9. https://doi.org/10.1037/h0024514
64. Seligman ME. Learned helplessness. Annu Rev Med. (1972); 23:407-412. https://doi.org/10.1146/annurev.me.23.020172.002203
65. Maier SF, Seligman ME. Learned helplessness at fifty: insights from neuroscience. Psychol Rev. (2016); 123(4):349-367. https://doi.org/10.1037/rev0000033
66. Abelaira HM, Réus GZ, Quevedo J. Animal models as tools to study the pathophysiology of depression. Braz J Psychiatry. (2013); 35(2):112-120. https://doi.org/10.1590/1516-4446-2013-1098
67. Czéh B, Fuchs E, Wiborg O, Simon M. Animal models of major depression and their clinical implications. Prog Neuropsychopharmacol Biol Psychiatry. (2016); 64:293-310. https://doi.org/10.1016/j.pnpbp.2015.04.004
68. O’Neil MF, Moore NA. Animal models of depression: are there any?. Hum Psychopharmacol. (2003); 18(4):239-254. https://doi.org/10.1002/hup.496
69. Duman CH. Models of depression. Vitam Horm. (2010); 82:1-21. https://doi.org/10.1016/S0083-6729(10)82001-1
70. Andersen SL. Exposure to early adversity: Points of cross-species translation that can lead to improved understanding of depression. Dev Psychopathol. (2015); 27(2):477-491. https://doi.org/10.1017/S0954579415000103
71. Čater M and Majdič G. How early maternal deprivation changes the brain and behavior?. Eur J Neurosci. (2022); 55(9-10):2058-2075. https://doi.org/10.1111/ejn.15238
72. Hao Y, Ge H, Sun M, Gao Y. Selecting an appropriate animal model of depression. Int J Mol Sci. (2019); 20(19):4827. https://doi.org/10.3390/ijms20194827
73. Takahashi A. Toward Understanding the Sex Differences in the Biological Mechanism of Social Stress in Mouse Models. Front Psychiatry. (2021); 12:644161. https://doi.org/10.3389/fpsyt.2021.644161
74. Willner P. Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology. (2005); 52(2):90-110. https://doi.org/10.1159/000087097
75. Antoniuk S, Bijata M, Ponimaskin E, Wlodarczyk J. Chronic unpredictable mild stress for modeling depression in rodents: meta-analysis of model reliability. Neurosci Biobehav Rev. (2019); 99:101-116. https://doi.org/10.1016/j.neubiorev.2018.12.002
76. Katz RJ, Roth KA, Carroll BJ. Acute and chronic stress effects on open field activity in the rat: implications for a model of depression. Neurosci Biobehav Rev. (1981); 5(2):247-251. https://doi.org/10.1016/0149-7634(81)90005-1
77. Katz RJ. Animal model of depression: pharmacological sensitivity of a hedonic deficit. Pharmacol Biochem Behav. (1982); 16(6):965-968. https://doi.org/10.1016/0091-3057(82)90053-3
78. Willner P. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol Stress. (2016); 6:78-93. https://doi.org/10.1016/j.ynstr.2016.08.002
79. Alizadeh Makvandi A, Khalili M, Roghani M, Amiri Moghaddam S. Hesperetin ameliorates electroconvulsive therapy-induced memory impairment through regulation of hippocampal BDNF and oxidative stress in a rat model of depression. J Chem Neuroanat. (2021); 117:102001. https://doi.org/10.1016/j.jchemneu.2021.102001
80. El-Marasy SA, El Awdan SA, Hassan A, Ahmed-Farid OA, Ogaly HA. Anti-depressant effect of cerebrolysin in reserpine-induced depression in rats: Behavioral, biochemical, molecular and immunohistochemical evidence. Chem Biol Interact. (2021); 334:109329. https://doi.org/10.1016/j.cbi.2020.109329
81. Arioz BI, Tastan B, Tarakcioglu E, et al. Melatonin attenuates LPS-induced acute depressive-like behaviors and microglial NLRP3 inflammasome activation through the SIRT1/Nrf2 pathway. Front Immunol. (2019); 10:1511. https://doi.org/10.3389/fimmu.2019.01511
82. Zhao X, Cao F, Liu Q, et al. Behavioral, inflammatory and neurochemical disturbances in LPS and UCMS-induced mouse models of depression. Behav Brain Res. (2019); 364:494-502. https://doi.org/10.1016/j.bbr.2017.05.064
83. Leonard BE. The olfactory bulbectomized rat as a model of depression. Pol J Pharmacol Pharm. (1984); 36(5):561-569.
84. Yin R, Zhang K, Li Y, et al. Lipopolysaccharide-induced depression-like model in mice: meta-analysis and systematic evaluation. Front Immunol. 2023;14:1181973.
85. Song C, Leonard BE. The olfactory bulbectomised rat as a model of depression. Neurosci Biobehav Rev. (2005); 29(4-5):627-647. https://doi.org/10.1016/j.neubiorev.2005.03.010
86. Kelly JP, Wrynn AS, Leonard BE. The olfactory bulbectomized rat as a model of depression: an update. Pharmacol Ther. (1997); 74(3):299-316. https://doi.org/10.1016/s0163-7258(97)00004-1
87. Read JR, Sharpe L, Modini M, Dear BF. Multimorbidity and depression: a systematic review and meta-analysis. J Affect Disord. (2017); 221:36-46. https://doi.org/10.1016/j.jad.2017.06.009
88. Krishnan V, Nestler EJ. Animal models of depression: molecular perspectives. Curr Top Behav Neurosci. (2011); 7:121-147. https://doi.org/10.1007/7854_2010_108
89. Czéh B, Simon M. Benefits of animal models to understand the pathophysiology of depressive disorders. Prog Neuropsychopharmacol Biol Psychiatry. (2021); 106:110049. https://doi.org/10.1016/j.pnpbp.2020.110049