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Reliability of the chronic mild stress model of depression: A user survey
Open accessAbstract
The chronic mild stress (CMS) model of depression is considered by many to be the animal model of depression that has the greatest validity and translational potential, but it has often been criticized for a perceived lack of reliability. The aims of this study were to establish the extent to which the procedure is reproducible, and to identify experimental variables relevant to its reliability. Because failures to replicate frequently remain unpublished, a survey methodology was used. A questionnaire was circulated to 170 labs identified from a PubMed search as having published a CMS study in the years 2010 or 2015 (with no selection in respect of the results reported). Responses were returned by 71 (42%) of the recipients, followed by further correspondence with some of them. Most of the respondents (n = 53: 75%) reported that the CMS procedure worked reliably in their hands. Of the others, 15 (21%) reported that the procedure was usually reliable, but not always (n = 9: 13%) or not for all measures (n = 6: 8%). Only three respondents (4%) reported being unable to reproduce the characteristic effects, two of whom may be using an insufficient duration of CMS exposure. A series of analyses compared the 75% of 'reliable' labs with the 25% of 'less reliable' labs on a range of experimenter, subject, stress and outcome variables. Few if any significant differences between these two samples were identified, possibly because of the small size and diversity of the 'less reliable' sample. Two other limitations of the study include the (unavoidable) omission of labs that may have worked with the model but not published their data, and the use of ad hoc measures to compare the severity of different stress regimes. The results are discussed in relation to relevant published observations. It is concluded that CMS is in fact a rather robust model, but the factors that result in a less effective implementation in a minority of laboratories remain to be firmly established.
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“Chronic unpredictable/mild/variable stress and chronic social defeat stress are the two most commonly used animal models of depression [31, 34–38].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [38]
In the citing paper
“The induction of anhedonia has been the primary focus in this model”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [38]
In the citing paper
“has been the most consistent biological abnormality in this disorder [38, 40].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [38]
In the citing paper
“chronic unpredictable/mild/variable stress induces a myriad of behavioral, neurochemical, and neuroendocrine alterations that mirror changes mainly observed in human depression [38].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [38]
In the citing paper
“along with its important feature reproducing hypercortisolism, which is found in 40–60% of patients with major depression”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [38]
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Citations
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BackgroundMethodSelf-citation
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“In our study, we applied a chronic mild stress (CMS) protocol, the most extensively validated [35], to induce depressive-like behavior.”
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“Chronic social defeat stress (CSDS) and chronic mild stress models have been widely used to investigate the underlying mechanisms and etiology of depression (Willner 2016; Venzala et al. 2012).”
A Glimpse Into the Sexual Dimorphisms in Major Depressive Disorder Through Epigenetic Studies
Cahill, B., Poelker-Wells, S., Prather, J. F., & Li, Y. (2021) · Frontiers in Neural Circuits · doi:10.3389/fncir.2021.768571 · Cited by 11
“Other variations of the CVS model include the chronic mild stress model (CMS) (Willner, 2017), as well as unpredictable variable stress models (Kessler, 1997; Kendler et al., 1999).”
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BackgroundSplenectomy does not affect mouse behaviors
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“To induce stress-related anhedonia we used the chronic unpredictable stress (CUS) paradigm, a widely accepted animal model of depression that is associated with HPA axis chronic hyperstimulation (Willner, 1997, 2017a, b).”
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“Thus, the UCMS protocol is meant to reflect the continuous pressures humans are exposed to in everyday life, modeling MDD with good face validity (Willner, 2017a, 2017b).”
Romanò, N., & Menzies, J. R. W. (2025) · Journal of Neuroendocrinology · doi:10.1111/jne.70051 · Cited by 9
“More recently, a wider and arguably more impactful range of stressors have been introduced; for example, physical restraint, exposure to cold or heat, removal of cage bedding, exposure to hypoxia, noise, strobo-scopic lighting or predator odours, and social isolation or overcrowding.”
How the Sucrose Preference Succeeds or Fails as a Measurement of Anhedonia
Strekalova, T. V. (2022) · Neuromethods · doi:10.1007/978-1-0716-2748-8_6 · Cited by 8
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“…face validity (it is related to anhedonia, weight reduction, and alterations in the hippocampus, prefrontal areas, and the normal functioning of the HPA axis), and construct validity (as chronic exposure to stress is an important risk factor for developing depression)(Willner,2017a; 2017b).”
BackgroundA book recommendation algorithm based on collaborative filtering
Zhu, Y. (2016) · International Conference on Computer Science and Network Technology (ICCSNT) · doi:10.1109/iccsnt.2016.8070165 · Cited by 8
“Models can be used to test and compare various scenarios of behavioral responses and management decisions [5].”
BackgroundPsychological stress disturbs bone metabolism via miR-335-3p/Fos signaling in osteoclastPreprint
Zhang, J., Li, J., Huang, J., Xiang, X., Li, R., Zhai, Y., Lin, S., & Liu, W. (2024) · eLife · doi:10.7554/elife.95944 · Cited by 8
“CUMS was carried out as described previously(Antoniuk et al., 2019; Willner, 2017) with slight modifications, and the stimulations included 24-hour food deprivation, 24-hour water deprivation, 1 min tail pinch, 7-hour 45° cage tilt, 24-hour wet cage, 5 minutes forced swimming, 5-hour physical…”
Virijević, K., Spasojević, N., Stefanović, B., Ferizović, H., Janković, M., Vasiljevic, P. J., & Dronjak, S. (2024) · Neuroscience Letters · doi:10.1016/j.neulet.2024.137709 · Cited by 9
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Potrebić, M., Pavković, Ž., Lončarević‐Vasiljković, N., Kanazir, S., & Pešić, V. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110186 · Cited by 6
“Sucrose consumption and preference for palatable solutions displays “liking” (consummatory) capacity of hedonic response (Der-Avakian and Markou, 2012; Willner, 2017).”
BackgroundHan, M., Zhou, Y., Gao, X., Cheng, X., Deng, L., Ji, S., Li, Z., Cai, Y. C., Yan, C., & Chen, Y. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1635897 · Cited by 7
“Mice were kept in individual cages and exposed to the CUMS program (Willner, 2017; Zhou et al., 2022).”
Cui, Y., Ursuliak, Z., & Rupasinghe, H. P. V. (2025) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2025.111567 · Cited by 6
Salvianolic Acids Alleviate Chronic Mild Stress-Induced Depressive-Like Behaviors in Rats
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“In this study, we used a wellestablished CMS protocol to induce depressive symptoms in rats [21].”
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“This experimental model has been classically used to elicit depressive behavior in mice [84,85].”
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“The model is considered to be realistic and with a high validity (Willner, 2017).”
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Martins‐Macedo, J., Mateus‐Pinheiro, A., Alves, C. S. C., Veloso, F., Gomes, E. D., Ribeiro, I., Correia, J. S., Silveira‐Rosa, T., Alves, N. D., Rodrigues, A. J., et al. (2023) · Cells · doi:10.3390/cells12030381 · Cited by 4
“Because stress is one of the most potent precipitating factors of depression, animal models of depression based on stress exposure, namely uCMS, are one of the most widely used [14,32].”
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“Importantly, patients tend to perceive a series of SLE instead of just one, wich is consistent with the chronic mild stress model of depression [50].”
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“That said, the UCMS model has been criticized for a lack of inter-laboratory reliability in behavioral response [48].”
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Investigating the role of GPR39 in treatment of stress-induced depression and anxiety
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“The striking results of the survey conducted by Willner himself leave us wondering whether a large amount of negative data is simply not being reported (Willner 2017).”
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“Therefore, the published data could represent the tip of an iceberg with evidence of unreliability below the surface, and truthfulness of data may be compromised by a large amount of unpublished records (Du Preez et al., 2021b; Markov, 2022; Willner, 2017a).”
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“UCMS is an established, validated protocol for generating stress in rodents, inducing behavioral changes that correlate with increased anxiety-like and depressive-like symptoms (Willner, 2017; Willner, 2017).”
BackgroundMethodInfluentialMozart K488 Addition Can Improve Depressive-Like Behavior in Rats: In Search of Better Management
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“15 The most consistent effect observed after several weeks of CUMS administration was a decrease in sucrose consumption assessed by SPT. 28 However, this decrease was reversed with the use of antidepressant treatment.”
Mondragón-García, A., Ramírez-Sánchez, E., Francia-Ramírez, D., Hernández-González, O., Rojano-Posada, Y., Ortega-Tinoco, S., Garduño, J., Verdugo-Díaz, L., & Hernández-López, S. (2024) · Neuroscience · doi:10.1016/j.neuroscience.2024.10.043 · Cited by 2
“…(1 mg/kg) improved the depression phenotype by employing widely used tests to assess depressive-like behaviors in rats, including the sucrose preference test, forced swim test, and open field test (Yan et al., 2010; Krishnan and Nestler, 2011; Willner, 2016; Sahin, 2023; Verharen et al., 2023).”
Depoortère, R., Papp, M., Gruca, P., Litwa, E., Łasoń, M., Biała, D., & Newman‐Tancredi, A. (2024) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000809 · Cited by 2
“…rodents (Willner, 1997), ketamine opposes the CMS-induced deficit in sucrose consumption (a behavioral marker of anhedonia) and attenuates the disruption of working memory, as assessed by the novel object recognition (NOR) test (Willner, 2017a, 2017b; Antoniuk et al ., 2018; Papp et al ., 2023).”
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“Thus, the activation of the lateral habenula nucleus, which is very well known in the management of negative emotions (aversion) via its projections towards the VTA and the raphe nucleus, consists respectively in the decrease of dopamine and 5HT production in the mesocorticolimbic pathway, this decreases the preferenc…”
BackgroundmGlu Receptor Modulation in Murine Models of Stress and Affective Disorders
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“Based on our experience, the success of using CUMS models appears to be dependent on the interplay among three factors: (i) individual differences in susceptibility to stress, both within and among animal populations, (ii) overall severity of microstressors applied, which need to be intense enough to evoke a stress re…”
MethodPostmenopausal Status Exacerbates Stress-Related Neurological Disorders in Rats
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Experimental Animal Models for Depressive Disorders: Relevance to Drug Discovery
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Network Models in Neuroscience
Bassett, D. S., Zurn, P., & Gold, J. I. (2019) · The MIT Press eBooks · doi:10.7551/mitpress/12593.003.0011 · Cited by 1
“Intuitively, descriptive validity requires that the model resemble the system under study, a concept akin to face validity in animal models [99].”
BackgroundYakovleva, O. V., Bogatova, K., Skripnikova, V. V., & Ситдикова, Г. Ф. (2022) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-022-01231-5 · Cited by 1
Efeitos comportamentais e neuroplásticos da combinação de escitalopram e canabinóides
Scarante, F. F. (2018) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/d.17.2018.tde-25072018-103829
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Chatterjee, D. (2019) · TSpace (University of Toronto)
Characterizing behavior changes in mice receiving splenectomyPreprint
Guan, J., Zhang, P.-S., Zhang, W.-C., Zhang, B.-Q., Wu, H.-T., Lan, Y., & Yuan, T. (2022) · Research Square · doi:10.21203/rs.3.rs-1401302/v1
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Efeitos do estresse crônico moderado sobre a manutenção de uma discriminação operante
Lima, A. V., Júnior, A. R. F., & Micheletto, N. (2023) · Revista Brasileira de Terapia Comportamental e Cognitiva · doi:10.31505/rbtcc.v25i1.1742
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Szalanczy, A., Fitzpatrick, M., Beeson, A., Bui, T., Dyson, C., Eller, S., Landry, J., Scott, C., Grzybowski, M. N., Klotz, J., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.24.546378
“Unpredictable Chronic Mild Stress (UCMS) UCMS is an established, validated protocol for generating stress in rodents, inducing behavioral changes that correlate with increased anxiety-like and depressive-like symptoms (Willner 2017, Willner 2017).”
BackgroundMethodInfluentialBelo-Silva, A. E., Silva, N. K. G. T., Marianno, P., Costa, G. D. A., da Rovare, V. P., Bailey, A., Munhoz, C. D., Novaes, L. S., & Camarini, R. (2023) · SSRN Electronic Journal · doi:10.2139/ssrn.4599032
Iwai, T., Mishima, R., Hirayama, S., Nakajima, H., Oyama, M., Watanabe, S., Fujii, H., & Tanabe, M. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13020608
“Individual stressors in CMS are exposed to animals at various timings and methods, depending on the laboratory [25].”
BackgroundPsychological stress disturbs bone metabolism via miR-335-3p/Fos signaling in osteoclast
Zhang, J., Li, J., Huang, J., Xiang, X., Li, R., Zhai, Y., Lin, S., & Liu, W. (2024) · eLife · doi:10.7554/elife.95944.3
Psychological stress disturbs bone metabolism via miR-335-3p/Fos signaling in osteoclastPreprint
Zhang, J., Li, J., Huang, J., Xiang, X., Li, R., Zhai, Y., Lin, S., & Liu, W. (2024) · eLife · doi:10.7554/elife.95944.1
StressMatic: Bridging innovation and reliability in animal models of stress
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Stressor Processes and Effects on Neurobiological Functioning
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Psychological stress disturbs bone metabolism via miR-335-3p/Fos signaling in osteoclastPreprint
Zhang, J., Li, J., Huang, J., Xiang, X., Li, R., Zhai, Y., Lin, S., & Liu, W. (2024) · eLife · doi:10.7554/elife.95944.2
Dai, T., Algar, S. D., SMALL, M. P., Zalesky, A., & Rodger, J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.05.667822
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Erkizia-Santamaría, I., Fernández, L., Horrillo, I., Meana, J. J., & Ortega, J. E. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.11.30.691402
“Therefore, the published data could represent the tip of an iceberg with evidence of unreliability below the surface, and truthfulness of data may be compromised by a large amount of unpublished records (Du Preez et al., 2021b; Markov, 2022; Willner, 2017a).”
InfluentialNadei, O. V. (2025) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1134/s0022093025060201
“To model DLB in rats, a chronic unpredictable mild stress (CUMS) procedure was used, which is considered one of the most effective for experimentally modeling this disorder [24].”
Peptide ACTH(6-9)-PGP Attenuates the Consequences of Chronic Unpredictable Stress in Male Rats
Dolotov, O. V., Yatsenko, K. A., Andreeva, L. A., Myasoedov, N. F., & Grivennikov, I. A. (2025) · Neurochemical Journal · doi:10.1134/s1819712425700758
Nadei, O. V., & Prokopenko, E. S. (2026) · Journal of Molecular Neuroscience · doi:10.1007/s12031-026-02491-3
“The CUMS protocol, which has been recognized as one of the most effective for experimental modeling of depression, was employed to simulate DLB in rats (Willner 2017).”
Romanò, N., & Menzies, J. R. W. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.27.714712
Jeandel, J. (2019) · theses.fr (ABES) · doi:10.70675/ef224fafzdd92z415ezbe2ez1ee2a696f766
Impact of gut microbiota in Chagas disease: a contemporary overview
Garima, Thakur, R., & Kaur, S. (2026) · Journal of Parasitic Diseases · doi:10.1007/s12639-026-01957-w
Benneh, C. K., Abotsi, W. K. M., Moomin, A., Biney, R. P., Ofosu, J. O., Abeka, M. K., Tandoh, A., Adongo, D. W., & Woode, E. (2026) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-026-05501-8
“Chronic models, which better replicate the neuroinflammatory and molecular hallmarks of human depression (Willner 2017), suggest that the current dosing regimen of dXA may not be sufficient for sustained therapeutic reversal.”
Kılıç, A., Ipek, B. E., Çimen, Y. A., Yilmaz, M., Cimen, F. B. K., Hekimoğlu, E. R., Dedeakayoğulları, H., & Üstünova, S. (2026) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-026-05612-2
“This elevation mirrors the sustained increase in corticosterone reported in the literature during 20 to 60 days of stress, representing an exhaustion phase in which the organism can no longer effectively counter the effects of stress (Willner 2017).”
Meagher, R. K., & Fureix, C. (2026) · Wiley eBooks · doi:10.1002/9781394182237.ch9
Banasr, M., Bansal, Y., Mitchell, M., Codeluppi-Arrowsmith, S., Knoch, J., Clifford, K. P., Nikolova, Y. S., & Sibille, E. L. (2026) · Research Square · doi:10.21203/rs.3.rs-10397993/v1
Dubljević, O., Popović, D., Potrebić, M., Petković, B. B., Brdarić, E., Richter, F., & Pešić, V. (2026) · Translational Psychiatry · doi:10.1038/s41398-026-04306-w
“…active coping with an imposed stressful situation [36]; 4) sucrose preference test (SPT), to assess consummatory aspect of hedonic response [38, 39], along with food intake as an apathy-related behavior [40]; food consumption as a goal-directed and motivated behavior indispensable for…”
Miller, E. C., Bork, T., McCall, C., Allen, K., Hoover, C., Nemeth, C., Eby, A., Borrelli, H., Vandiver, V., Trollip, L., et al. (2026) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2026.111871
Komnenov, D., Uthman, Y., Ramirez, N., & Banek, C. T. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.08.04.742819
Lamba, D., Chauhan, S., Dhingra, D., & Bansal, S. (2026) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2026.174276
Metadata
- Authors
- Willner, P.
- Affiliations
- Swansea University (GB)
- Corresponding author
- Willner, Paul
- ORCID
- Willner, Paul
- Venue
- Neurobiology of Stress
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 6
- Pages
- 68-77
- ISSN
- 2352-2895 (ISSN-L)
- PMC
- PMC5314419
- OpenAlex
- W2510666910
- Cited by
- 198
- References
- 91
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 27 · 2023: 22 · 2022: 31 · 2021: 25 · 2020: 17 · 2019: 20 · 2018: 19 · 2017: 5
- FWCI
- 9.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Neurobiology of Stress (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Keywords
- chronic mild stress, animal models of depression, reproducibility, reliability statistics, replication failure, stressor severity, translational validity
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