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Animal models of major depression and their clinical implications
Abstract
Major depressive disorder is a common, complex, and potentially life-threatening mental disorder that imposes a severe social and economic burden worldwide. Over the years, numerous animal models have been established to elucidate pathophysiology that underlies depression and to test novel antidepressant treatment strategies. Despite these substantial efforts, the animal models available currently are of limited utility for these purposes, probably because none of the models mimics this complex disorder fully. It is presumable that psychiatric illnesses, such as affective disorders, are related to the complexity of the human brain. Here, we summarize the animal models that are used most commonly for depression, and discuss their advantages and limitations. We discuss genetic models, including the recently developed optogenetic tools and the stress models, such as the social stress, chronic mild stress, learned helplessness, and early-life stress paradigms. Moreover, we summarize briefly the olfactory bulbectomy model, as well as models that are based on pharmacological manipulations and disruption of the circadian rhythm. Finally, we highlight common misinterpretations and often-neglected important issues in this field.
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“Chronically stressed rodents have reduced reward preference, as measured by a loss of preference for sucrose solutions and time spent interacting with a novel con-specific.”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [7]
In the citing paper
“Stressed animals also tend to spend less time struggling against inescapable stressors such as forced swimming or tail suspension.”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [7]
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“Chronic unpredictable mild stress (CUMS) is considered to be one of the most extensively validated animal model of depression that meets good face, construct and predictive validity criteria (7-9).”
BackgroundOrdyan, N. E., Malysheva, O., Акулова, В. К., Kholova, G. I., & Пивина, С. Г. (2021) · Integrative Physiology · doi:10.33910/2687-1270-2021-2-1-61-70 · Cited by 4
“Такой режим электрокожной стимуляции создает неизбегаемость и неконтролируемость воздействия, в результате чего у животного формируется состояние «выученная беспомощность», характеризующееся рядом поведенческих и гормональных нарушений, воспроизводящих симптоматику депрессии у людей (Czén et al. 2016).”
Influentialde Abreu, M. S., Giacomini, A. C. V. V., Genário, R., Demin, K. A., Amstislavskaya, T. G., Costa, F. V., Rosemberg, D. B., Sneddon, L. U., Strekalova, T. V., Soares, M. C., et al. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2021.136382 · Cited by 4
Qian, L., Zhang, S., Lin, C., Lin, J., & Li, Z. (2024) · International Journal of Cardiology · doi:10.1016/j.ijcard.2024.132505 · Cited by 4
MacKinnon, D. F., & Chen, L. N. (2024) · Springer eBooks · doi:10.1007/978-3-030-51366-5_20 · Cited by 5
Antidepressant-like effect of Albizia zygia root extract in murine models
Kumbol, V. W.-A., Abotsi, W. K. M., & Biney, R. P. (2020) · Journal of Basic and Clinical Physiology and Pharmacology · doi:10.1515/jbcpp-2019-0310 · Cited by 4
Hemanny, C., Moura, I., Mello, M., Figueiredo, A. M., Demarzo, M., & de Oliveira, I. R. (2023) · Middle East Current Psychiatry · doi:10.1186/s43045-023-00321-5 · Cited by 5
Acoustilytix™: A Web-Based Automated Ultrasonic Vocalization Scoring Platform
Ashley, C. B., Snyder, R. D., Shepherd, J. E., Cervantes, C., Mittal, N., Fleming, S. M., Bailey, J., Nievera, M. D., Souleimanova, S. I., Nyaoga, B. M., et al. (2021) · Brain Sciences · doi:10.3390/brainsci11070864 · Cited by 3
“Animal models allow direct measurement and manipulation of the neural circuitry that drives emotional processing, circuitry that often can only be inferred in human studies [1–5].”
BackgroundCritical period plasticity is associated with resilience to short unpredictable stress
Williams, R., van den Oord, C., Lee, E. N., Fedde, S. C., Oscherwitz, G. L., & Ribic, A. (2025) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2025.1584240 · Cited by 3
The Olfactory Bulbectomy Model of Depression: Brief History, Current Status and Critique
Coppola, D. M. (2025) · Brain Sciences · doi:10.3390/brainsci15080775 · Cited by 3
Catapol: a promising natural neuroprotective agent for neurologic disorders
Li, W., & Zhou, X. (2025) · Acta Materia Medica · doi:10.15212/amm-2024-0097 · Cited by 3
“…abovementioned studies, depression models were primarily developed using male rodents, despite epidemiologic evidence clearly showing that women are significantly more susceptible to stress-related mental health disorders and that depression is at least twice as prevalent in women as in men [62].”
McKenzie, T. M. L., Bellato, A., Ismail, K., & Fernandes, C. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03138-2 · Cited by 4
“To comprehensively assess the impact of different stressors in rodent models of depression, secondary outcome measures included behavioural readouts [36], stress-related hormones, key brain metabolites and cellular phenotypes previously reported association with depression [9, 37].”
Animal Models of Depression: Classification and Relevant Validation Criteria
Herrero, S. M., Hernández, J. I., Soler, O. M., Guevara, M. A., & Gargiulo, P. Á. (2018) · Springer eBooks · doi:10.1007/978-3-319-95360-1_19 · Cited by 3
Ramírez-Boix, P., & Giménez‐Llort, L. (2019) · Experimental Gerontology · doi:10.1016/j.exger.2019.03.004 · Cited by 3
Вальдман, Е. А., Крайнева, В. А., Олеговна, К. С., & Садовский, М. С. (2021) · Journal Biomed · doi:10.33647/2074-5982-17-2-22-34 · Cited by 3
Cezarotto, V. S., Ferreira, L. M., Dal'Pupo, R. P., dos Santos, A., Santos, K. F., Linares, C. E. B., Stein, A. C., Sari, M. H. M., & Cruz, L. (2022) · Chemistry & Biodiversity · doi:10.1002/cbdv.202200514 · Cited by 3
“Stressed animals usually showed depressive-like phenotypic behavior, that can be restored to normal levels by repeated treatment with antidepressant drugs.([39,40]) The models that are based on environmental or social stressors are highly relevant in researching and comprehending the pathophysiology of depression.”
BackgroundXue, B., Ma, Y.-Y., Zhu, J.-Y., Mu, Y., Li, Y., Shen, F., Liang, J., & Zhang, J. (2023) · Animal Cognition · doi:10.1007/s10071-023-01798-7 · Cited by 3
“Both of these models mimic socio-environmental or social conflict stressors in everyday life, resulting in a long-term depression-like phenotype similar to that observed in clinical patients (Becker et al. 2021; Czéh et al. 2016; Planchez et al. 2019).”
ResultWang, C. K., Kim, G., Aleksandrova, L. R., Panenka, W. J., & Barr, A. M. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1387158 · Cited by 3
Moraga‐Amaro, R., Vazquez-Matias, D. A., Nazario, L. R., Dierckx, R., Stehberg, J., Doorduin, J., & de Vries, E. F. J. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106727 · Cited by 3
“The RSD model of depression is a widely used model of chronic stress in male rats with high face and construct validity (Cz ´ eh et al., 2016).”
MethodToward a diagnostic framework for the equine depressive phenotype: A narrative review
Brien, C. O., Parker, M. O., & McBride, S. D. (2025) · Journal of Veterinary Behavior · doi:10.1016/j.jveb.2025.04.004 · Cited by 3
Genetic animal models for psychiatric disorders
Zhou, Y., Samsom, J., & Wong, A. H. C. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-819602-1.00015-2 · Cited by 4
Non-neuronal brain biology and its relevance to animal welfare
Lawrence, A. B., Brown, S. M., Bradford, B. M., Mabbott, N. A., Bombail, V., & Rutherford, K. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106136 · Cited by 3
“Corroborating evidence from animals comes mainly from studies of chronic stress (see Cz ´ eh et al., 2016 for a critical review of animal research on anxiety and depression).”
So, T. W., Choi, H. Y., Xu, H., Zhu, J., Shi, L., & Ip, J. P. K. (2025) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2025.03.008 · Cited by 3
“Other depressive-like behaviours such as behavioural despair and altered locomotor activity, which are commonly tested by forced swim test and tail suspension test, can resemble patients ’ symptoms of fatigue or loss of energy (Becker et al., 2021; Cz ´ eh et al., 2016).”
Ávila, A., Riveros, M. E., Adasme, S., Guevara, C., Río, R. D., Ortíz, F. C., Leibold, N. K., & Ezquer, F. E. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17091129 · Cited by 2
Dafale, R. S., Kamath, S. U., Bhasin, G., Vasanthalaxmi, K., Bose, U., G, R. B. M., Punja, D., Bharadwaj, A., & Manjula, S. D. (2025) · Nutritional Neuroscience · doi:10.1080/1028415x.2025.2573226 · Cited by 2
“In addition, animal models make it possible to understand the pathophysiology, mechanism of action, and signaling pathways [15].”
Wei, X., Lu, Y., Guo, Z., Zhu, Z., Xia, C., Xu, M., Du, L.-X., Yang, Y., Shu, S., Wang, Z., et al. (2025) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2025.111666 · Cited by 2
Coutellier, L. D., Musazzi, L., & Pavlovic, Z. M. (2022) · Springer eBooks · doi:10.1007/978-3-030-87480-3_4 · Cited by 2
Etiopathogenesis of depression and experimental depression models used in preclinical studies
Kandemir, Ü. (2023) · European Journal of Life Sciences · doi:10.55971/ejls.1327521 · Cited by 2
“Various stressors such as social isolation or crowded housing, water or food deprivation, changing the light/dark cycle, cage tilting, and wet bedding are chronically applied to experimental animals throughout the CUMS protocol [67].”
InfluentialKorczyńska, J., Szczuka, A., Urzykowska, J., Kochanowski, M., Andrzejczyk, N. G., Piwowarek, K. J., & Godzińska, E. J. (2023) · Animals · doi:10.3390/ani13172734 · Cited by 2
MacKinnon, D. F., & Chen, L. N. (2023) · Springer eBooks · doi:10.1007/978-3-030-42825-9_20-1 · Cited by 2
Dragon, J., Gołyszny, M. J., Zielinski, M. W., Popiołek-Barczyk, K., Starowicz, K., & Obuchowicz, E. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.01.001 · Cited by 3
Dragon, J., Gołyszny, M., & Obuchowicz, E. (2025) · Pharmacology, Biochemistry and Behavior · doi:10.1016/j.pbb.2025.174000 · Cited by 2
Moreno, M., Martín-González, E., & Dalley, J. W. (2025) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/j.jpet.2025.103710 · Cited by 2
“10 — 12 As discussed further, the most widely used procedures in rodents include maternal separation (MS), limited bedding and nesting material (LBN), prenatal stress (PS), and early social stress.”
Metadata
- Authors
- Czéh, B., Fuchs, E., Wiborg, O., & Simon, M.
- Affiliations
- Aarhus University (DK)
- German Primate Center (DE)
- University of Pecs (HU)
- Corresponding author
- Czéh, Boldizsár
- Venue
- Progress in Neuro-Psychopharmacology and Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 64
- Pages
- 293-310
- ISSN
- 0278-5846 (ISSN-L)
- OpenAlex
- W1978343268
- Semantic Scholar
- 0da6df41578259009c908495102e570eae27700e
- Cited by
- 375
- References
- 233
- Citations by year
- 2026: 9 · 2025: 41 · 2024: 19 · 2023: 43 · 2022: 47 · 2021: 48 · 2020: 46 · 2019: 34 · 2018: 30 · 2017: 31 · 2016: 22
- FWCI
- 20.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Progress in Neuro-Psychopharmacology and Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- GRO (submittedVersion)
- Funders
- Hungarian Brain Research Program “B” (KTIA_NAP_13-2014-0019)
- Lundbeck Foundation (R83-A7631)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- major depressive disorder, animal models of depression, optogenetics, social stress, chronic mild stress, learned helplessness, early life stress, olfactory bulbectomy, circadian rhythm disruption, depression pathophysiology
- MeSH terms
- Animals, Brain, Depressive Disorder, Disease Models, Animal, Humans
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