Open Letter: End the Use of the Forced Swim Test

The forced swim test is widely discredited – it has been shunned by leading scientists and universities. Show your support for ending the use of the test by adding your name to the open letter, below. Please note that it may be shared with policymakers, decision-makers, and relevant media outlets.

Fill out the form below to add your name to the list of signatories of this open letter. If you have any questions or would like a copy of this letter to send on your own, please e-mail [email protected].

Open Letter

The forced swim test is not a valid or reliable scientific method, and its use must be ended.

The forced swim test (FST), or Porsolt test, is a behavioural experiment initially developed for screening antidepressant drugs¹ and which was later adopted in an attempt to model depression². It involves placing a small animal in a beaker filled with water that does not have an escape platform and recording the latency to stop swimming and the duration of floating^3-4. Historically, this observation has been interpreted as “behavioural despair”⁵ under the assumption that animals with depression-like behaviour “give up swimming earlier than those [who] are not depressed” and that antidepressant drugs reverse this effect⁶.

Its use in depression and anxiety research has been heavily criticised for various reasons. For example, rather than behavioural despair, floating in the FST may be indicative of learning, a way to conserve energy, or adaptation to a new environment^7-9. This has resulted in many institutional bodies advising against the use of the FST for modelling depression and/or anxiety^10-15. Additionally, its use as a screening tool is also under question, given that it cannot reliably predict the efficacy of antidepressant drugs^16-26. As a result, numerous pharmaceutical companies and universities have declared that they do not intend to use the FST in the future²⁷.

The FST has also been discouraged on the grounds of animal welfare – the UK’s National Centre for the Replacement, Refinement and Reduction of Animals in Research identifies the FST as “highly contentious” and “under considerable scrutiny” due to “its severity and effect on animal welfare”²⁸. Rodents often defecate during the procedure, which is thought to be a fear response²⁹, and there is a documented risk of accidental drowning or water aspiration³⁰. The test is considered acutely stressful for animals, which has resulted in it also being adopted to model post-traumatic stress disorder³¹. However, there are concerns about its validity for this purpose, too. Because of the neurobiological differences between humans and other animals, it is doubtful that the behaviour animals display when subjected to this experiment can be relevant to the human clinical condition^32-36.

Despite the scientific and welfare concerns, the test is still widely used, and many of those who fund, authorise, or use the FST appear not to be aware of the debate around its use and interpretation³⁷.

We, the undersigned, call for an end to the use of the FST. The FST should not pass a harm-benefit analysis and, consequently, there should be no further authorisation of the test in cases where it is known to be unfit for purpose. As well as causing harm to animals, continuing to authorise use of the FST undermines the integrity of scientific output and public confidence in the rigour with which scientific procedures on animals are evaluated and authorised.

I hereby sign this open letter:

Fields with an asterisk(*) are required.​

References

¹Porsolt RD, Anton G, Blavet N, et al. Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol. 1978;47(4):379-391. doi:10.1016/0014-2999(78)90118-8

²Molendijk ML, de Kloet ER. Forced swim stressor: trends in usage and mechanistic consideration. Eur J Neurosci. 2022;55(9-10):2813-2831. doi:10.1111/ejn.15139

³Castagné V, Porsolt RD, Moser P. Use of latency to immobility improves detection of antidepressant-like activity in the behavioral despair test in the mouse. Eur J Pharmacol. 2009;616(1-3):128-133. doi:10.1016/j.ejphar.2009.06.018

⁴Lucki I. Behavioral despair. In: Stolerman IP, ed. Encyclopedia of Psychopharmacology. Springer;2010:202-204. Accessed 1 June 2023. https://link.springer.com/referenceworkentry/10.1007/978-3-540-s68706-1_141

⁵Yankelevitch-Yahav R, Franko M, Huly A, et al. The forced swim test as a model of depressive-like behavior. J Vis Exp. 2015;97:e52587. doi:10.3791/52587

⁶Kraeuter AK, Guest PC, Sarnyai Z. The forced swim test for depression-like behavior in rodents. In: Guest P, ed, Pre-Clinical Models. Methods in Molecular Biology, vol 1916. Humana Press;2019:75-80. doi:10.1007/978-1-4939-8994-2_5

⁷Molendijk ML, de Kloet ER. Immobility in the forced swim test is adaptive and does not reflect depression. Psychoneuroendocrinology. 2015;62:389-391. doi:10.1016/j.psyneuen.2015.08.028

⁸Molendijk ML, de Kloet ER. Coping with the forced swim stressor: current state-of-the-art. Behav Brain Res. 2019;364:1-10. doi:10.1016/j.bbr.2019.02.005

⁹Commons KG, Cholanians AB, Babb JA, et al. The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem Neurosci. 2017;8(5):955-960. doi:10.1021/acschemneuro.7b00042

¹⁰Animals in Science Committee. Research and analysis: advice on the use of the forced swim test. Animals in Science Committee response to a ministerial commission for advice. July 2023. Accessed 5 July 2023. https://www.gov.uk/government/publications/advice-on-the-use-of-the-forced-swim-test. Published 5 July 2023

¹¹Sewell F, Waterson I, Jones D, et al. Preclinical screening for antidepressant activity – shifting focus away from the forced swim test to the use of translational biomarkers. Regul Toxicol Pharmacol. 2021;125:105002. doi:10.1016/j.yrtph.2021.105002

¹²British Association for Psychopharmacology, Laboratory Animal Science Association, The Physiological Society, and Understanding Animal Research. Factsheet on the forced swim test. 2020. Accessed 28 July 2023. https://www.lasa.co.uk/wp-content/uploads/2020/10/Forced-Swim-Test-Factsheet-final-002.pdf

¹³Use of primates and other animals in medical research in New South Wales. New South Wales Parliament, Legislative Council, Portfolio Committee No.2, Health; 2022. Accessed 28 July 2023. https://www.parliament.nsw.gov.au/lcdocs/inquiries/2857/Report%20No.%2059%20-%20PC%202%20-%20Use%20of%20primates%20and%20other%20animals%20in%20medical%20research%20in%20New%20South%20Wales.pdf

¹⁴Parliament of New South Wales. New South Wales Government Response: Inquiry into the use of primates and other animals in medical research in New South Wales. January 2023. Accessed 1 June. 2023. https://www.parliament.nsw.gov.au/lcdocs/inquiries/2857/Government%20Response%20-%20Report%20No.%2059%20-%20PC%202%20-%20Use%20of%20primates%20and%20other%20animals%20in%20medical%20research%20in%20New%20South%20Wales.pdf

¹⁵New Zealand Parliament, Economic Development, Science and Innovation Committee. Petition: end the use of the forced swim test in New Zealand. 2020. Accessed 28 July 2023. https://www.parliament.nz/resource/en-NZ/SCR_95117/50c60dcb87e9ee8360c19c45739ff919854c66c8

¹⁶National Animal Ethics Advisory Committee. Comment on the Porsolt forced swim test. Reviewed November 2021. Accessed 28 July 2023. https://www.naeac.org.nz/advice-and-reports/?fbclid=IwAR1jJvSOckEQkW-R2

¹⁷Bogdanova OV, Kanekar S, D’Anci KE, et al. Factors influencing behavior in the forced swim test. Physio Behav. 2023;13(118):227-239. doi:10.1016/j.physbeh.2013.05.012

¹⁸Commons KG, Cholanians AB, Babb JA, et al. The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem Neurosci. 2017;8(5):955-960. doi:10.1021/acschemneuro.7b00042

¹⁹Hodge RD, Bakken TE, Miller JA, et al. Conserved cell types with divergent features in human versus mouse cortex. Nature. 2019;573(7772):61-68. doi:10.1038/s41586-019-1506-7

²⁰Jennings EM, Okine BN, Olango WM, et al. Repeated forced swim stress differentially affects formalin-evoked nociceptive behaviour and the endocannabinoid system in stress normo-responsive and stress hyper-responsive rat strains. Prog Neuropsychopharmacol Biol Psychiatry. 2016;64:181-189. doi:10.1016/j.pnpbp.2015.05.008

²¹Kara NZ, Stukalin Y, Einat H. Revisiting the validity of the mouse forced swim test: systematic review and meta-analysis of the effects of prototypic antidepressants. Neurosci Biobehav Rev. 2018;84:1-11. doi:10.1016/j.neubiorev.2017.11.003

²²Kokras N, Antoniou K, Mikail HG, et al. Forced swim test: what about females? Neuropharmacology. 2015;99:408-421. doi:10.1016/j.neuropharm.2015.03.016

²³Kraeuter AK, Guest PC, Sarnyai Z. The forced swim test for depression-like behavior in rodents. In: Guest P, ed. Pre-Clinical Models. Methods in Molecular Biology, vol 1916. Humana Press;2019:75-80. doi:10.1007/978-1-4939-8994-2_5

²⁴Mul JD, Zheng J, Goodyear LJ. Validity assessment of 5 day repeated forced-swim stress to model human depression in young-adult C57BL/6J and BALB/cJ mice. eNeuro. 2016;3(6)ENEURO.0201-16.2016. doi:10.1523/ENEURO.0201-16.2016

²⁵Manolova AO, Stepanichev MY, Gulyaeva NV, et al. Behavior of rats in a forced swimming test is not an unambiguous predictor for the development of anhedonia in chronic stress. Neurosci Behav Physi. 2019;49:1016-1021. doi:10.1007/s11055-019-00831-y

²⁶Possamai F, dos Santos J, Walber T, et al. Influence of enrichment on behavioral and neurogenic effects of antidepressants in Wistar rats submitted to repeated forced swim test. Prog Neuropsychopharmacol Biol Psychiatry. 2015;58:15-21. doi:10.1016/j.pnpbp.2014.10.017

²⁷Suman PR, Zerbinatti N, Theindl LC, et al. Failure to detect the action of antidepressants in the forced swim test in Swiss mice. Acta Neuropsychiatr. 2018;30(3):158-167. doi:10.1017/neu.2017.33

²⁸Trunnell ER, Carvalho C. The forced swim test has poor accuracy for identifying novel antidepressants. Drug Discov Today. 2021; 26(12):2898-2904. doi:10.1016/j.drudis.2021.08.003

²⁹People for the Ethical Treatment of Animals. Victories! PETA is ending near-drowning experiments on animals. PETA.org. Updated 2023. Accessed 28 July 2023. https://www.peta.org/features/peta-ends-near-drowning-tests-small-animals

³⁰National Centre for the Replacement, Refinement and Reduction of Animals in Research. The forced swim test is not a regulatory requirement for the development of new antidepressants. July 2021. Accessed 28 July 2023. https://nc3rs.org.uk/news/forced-swim-test-not-regulatory-requirement-development-new-antidepressants

³¹Sutherland RJ, McDonald RJ. Hippocampus, amygdala, and memory deficits in rats. Behav Brain Res. 1990;37(1):57-79. doi:10.1016/0166-4328(90)90072-m

³²Use of primates and other animals in medical research in New South Wales. New South Wales Parliament, Legislative Council, Portfolio Committee No.2, Health; 2022. Accessed 28 July 2023. https://www.parliament.nsw.gov.au/lcdocs/inquiries/2857/Report%20No.%2059%20-%20PC%202%20-%20Use%20of%20primates%20and%20other%20animals%20in%20medical%20research%20in%20New%20South%20Wales.pdf

³³Barroca NCB, Della Santa G, Suchecki D, et al. Challenges in the use of animal models and perspectives for a translational view of stress and psychopathologies. Neurosci Biobehav Rev. 2022;104(104771). doi:10.1016/j.neubiorev.2022.104771

³⁴National Centre for the Replacement, Reduction and Refinement of Animals in Research. The forced swim test is not a regulatory requirement for the development of new antidepressants. July 2021. Accessed 28 July 2023. https://nc3rs.org.uk/news/forced-swim-test-not-regulatory-requirement-development-new-antidepressants

³⁵People for the Ethical Treatment of Animals Foundation. The Research Modernisation Deal. Updated December 2022. Accessed 28 July 2023. https://www.peta.org.uk/wp-content/uploads/2020/05/PETA-Research-Modernisation-Deal-UK-EU-V1.3.pdf

³⁶Garner JP. The significance of meaning: why do over 90% of behavioral neuroscience results fail to translate to humans, and what can we do to fix it? ILAR J. 2014;55(3):438-456. doi:10.1093/ilar/ilu047

³⁷Jayne K, Trunnell E, Baines J, Carvalho C, Herrmann K, Stoddart G. Analysis of justifications for use of the forced swim test: lessons learned for future project authorisation. In preparation.