The DOI matches its Crossref record; 90 of the 91 references it cites were found in a registry or an index.
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 Because failures to replicate frequently remain unpublished, a survey methodology was used.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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In the citing paper
“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
Cites
Estimating the reproducibility of psychological science
Open Science Collaboration (2015) · Science · doi:10.1126/science.aac4716 · Cited by 8,515
Power failure: why small sample size undermines the reliability of neuroscience
Button, K. S., Ioannidis, J. P. A., Mokrysz, C., Nosek, B. A., Flint, J., Robinson, E. S. J., & Munafò, M. R. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3475 · Cited by 7,641 · cited 2×
“Problems with the original data include observer bias in non-blinded experiments, failure to repeat observations before publishing them, lack of legitimate controls, small sample sizes, use of inappropriate statistical tests, and selective publication of partial data sets (Begley, 2013; Button et al., 2013).”
MethodRaise standards for preclinical cancer research
Begley, C. G., & Ellis, L. M. (2012) · Nature · doi:10.1038/483531a · Cited by 2,979 · cited 1×
“For example, failure rates of 75e90% were found for attempts within the pharmaceutical industry to replicate preclinical studies (Prinz et al., 2011; Begley and Ellis, 2012); similarly, a failure rate of around two thirds was reported for attempts to replicate experiments published in high ranking…”
BackgroundKrishnan, V., Han, M.-H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., LaPlant, Q., Graham, A., Lutter, M., Lagace, D. C., et al. (2007) · Cell · doi:10.1016/j.cell.2007.09.018 · Cited by 2,307 · cited 1×
“…a more intense social stressor, repeated exposure to social defeat does elicit a sustained decrease in rewarded behaviour in rats (Willner et al., 1995; von Frietag et al., 2000; Rygula et al., 2005; Miczek et al., 2011) and mice (Krishnan et al., 2007; Yu et al., 2011; Zhang et al., 2015).”
BackgroundWillner, P., Towell, A., Sampson, D., Sophokleous, S., & Muscat, R. (1987) · Psychopharmacology · doi:10.1007/bf00187257 · Cited by 1,993
Self-citationBelieve it or not: how much can we rely on published data on potential drug targets?
Prinz, F., Schlange, T., & Asadullah, K. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3439-c1 · Cited by 1,888
Willner, P. (1997) · Psychopharmacology · doi:10.1007/s002130050456 · Cited by 1,832
Self-citationGenetics of Mouse Behavior: Interactions with Laboratory Environment
Crabbe, J. C., Wahlsten, D., & Dudek, B. C. (1999) · Science · doi:10.1126/science.284.5420.1670 · Cited by 1,666
Willner, P. (2005) · Neuropsychobiology · doi:10.1159/000087097 · Cited by 1,605
Self-citationChronic mild stress-induced anhedonia: A realistic animal model of depression
Willner, P., Muscat, R., & Papp, M. (1992) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(05)80194-0 · Cited by 1,160 · cited 2×
“%) said that their procedure was based on the original CMS publications (Willner et al., 1987, 1992), with others citing more recent studies from other labs.”
BackgroundMethodSelf-citation
Cited by
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The chronic mild stress (CMS) model of depression: History, evaluation and usage
Willner, P. (2017) · Neurobiology of Stress · doi:10.1016/j.ynstr.2016.08.002 · Cited by 959
“An accompanying paper (Willner, 2016) describes a survey of users of these procedures (as discussed further below).”
BackgroundMethodInfluentialSelf-citationAntoniuk, S., Bijata, M., Ponimaskin, E., & Wlodarczyk, J. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.12.002 · Cited by 750
“…CUMS paradigm to evaluate depressive-like behavior in rodents and identify strain-specific susceptibility to stress based on one of the main end points of this model, “anhedonia,” assessed by the sucrose preference test (Willner et al., 1987; Willner, 2017b) and sucrose intake (Papp et al., 1994).”
InfluentialOn the nature and use of models in network neuroscience
Bassett, D. S., Zurn, P., & Gold, J. I. (2018) · Nature reviews. Neuroscience · doi:10.1038/s41583-018-0038-8 · Cited by 392
Selecting an Appropriate Animal Model of Depression
Hao, Y., Ge, H., Sun, M., & Gao, Y. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194827 · Cited by 257
“It also showed that the quality of a CMS model can be elevated by training laboratory operators to use sophisticated techniques [51].”
BackgroundMaking Sense of Rodent Models of Anhedonia
Scheggi, S., Montis, M. G. D., & Gambarana, C. (2018) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyy083 · Cited by 220
“A recent review shows that different names of the model do not strictly relate to the severity of the stressors used or predictability of the stressors (Willner, 2017a), and they usually yield similar results than the original protocol.”
BackgroundMethodResultInfluential
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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