Statement in response to a letter from Lord Sharpe of Epsom responding to the Animals in Science Committee forced swim test report

In July 2023 the UK’s Animals in Science Committee (ASC) published guidance on the use of the forced swim test based on the review of 18 project licences that include the forced swim test and feedback from researchers and other stakeholders. On Tuesday 5 March 2024, Lord Sharpe of Epsom responded to the ASC force swim test report, setting out actions that the Home Office will take to implement the ASC’s recommendations. This includes further restriction of the use of the forced swim test, enhanced scrutiny to proposals to use the forced swim test and action to support the validation of suitable alternatives to enable a complete ban on the use of the forced swim test.

The forced swim test is a behavioural test which involves placing a rat or mouse into a small tank of water from which it cannot escape and where the water is deep enough that the animals cannot touch the bottom. If the rodent stops swimming, the mouth and nose remain above the waterline. This creates a situation where the animal can swim in an attempt to escape or remain immobile without drowning. The precise method used varies between groups but commonly involves a test length of five or six minutes. Time spent swimming/not swimming is measured. The test has been used for two main purposes: to assess the effect of antidepressants and to model depression.

The forced swim test is highly contentious and has come under considerable scrutiny. It is generally accepted that the test is stressful and, with no way to escape the container, can compromise animal welfare. The forced swim test is classified as ‘moderate’ severity by the UK regulator based on the characteristic feature that it causes a significant and easily detectable disturbance of an animal's normal state. This ‘moderate’ classification is considered an over-estimate by its advocates and an under-estimate of the impacts to the animals by its critics. In the absence of objective measures of the animal's experience, the level of stress remains the subject of debate. There are also concerns about the test’s scientific utility, including the lack of a mechanistic link with depression (i.e. there is no neurobiological correlation between the behaviour of animals and the effects seen in humans).

Screening for antidepressant treatments

The forced swim test has been used since the 1970s to assess the efficacy of antidepressants. All clinically used antidepressant treatments decrease immobility in the forced swim test. There is no regulatory requirement to perform the forced swim test but the results from it may form part of the body of evidence to support moving a drug to clinical trials. 

Concerns about the scientific validity of the forced swim test to screen for antidepressants include which drugs it is sensitive to and whether it is selective for antidepressants alone. Whether the forced swim test can detect the therapeutic potential of antidepressant drugs using novel mechanisms (i.e. not affecting the serotonergic or noradrenergic systems) is not known. Additionally, there have been recorded false positives where drugs have given an antidepressant-like effect in the forced swim test despite not being used as antidepressants in the clinic. The results of the test are also influenced by multiple factors such as the sex and strain of the animals used and the temperature of the water, making drug effects difficult to replicate across laboratories.

Modelling depression

Some groups have relied on the forced swim test as a model of depression itself. Depression is a multifaceted human psychiatric disorder, characterised by a variety of symptoms which include lowered mood, anhedonia (the loss of interest, enjoyment or pleasure from life's experiences), loss of energy, changes in weight and appetite, changes in sleep, a difficulty in concentrating, and suicidal ideation. The forced swim test does not provide a reliable model of depression or any of its symptoms.

There are alternative behavioural tests to assess animals’ emotional state and behaviours relevant to depression which have less harmful impacts on animal welfare. These include the sucrose preference test which can be used to assess anhedonia, and cognitive bias tests. The latter are based on work in humans that shows people experiencing negative emotions make more negative and pessimistic judgements about ambiguous events.

In 2021 the NC3Rs published a paper in collaboration with the UK’s medicines regulator the MHRA and other experts in the field focusing on the use of the forced swim test for screening antidepressants. The paper:

• Outlined the UK (and wider) regulatory perspectives on this test, clarifying that the forced swim test is not a regulatory requirement for the development of new antidepressants.
• Examined the scientific validity of the test, concluding that it may have utility as a screen for the development of antidepressant drugs but not as a model of depression.
• Highlighted concerns surrounding the severity of suffering for animals involved and opportunities to refine the test from an animal welfare perspective.
• Called for investment into alternative approaches to test antidepressant drugs and research depression.

Investment in alternative approaches

We have been funding the development and validation of alternative models of depression and mood disorders since 2011. This includes some projects that replace animal use. Most recently, we have funded a project to develop a larval zebrafish model of major depressive disorder to replace the use of rodents. Zebrafish larvae at non-protected early life stages* can be used to assess behaviours symptomatic of depression, including changes in sleep and reduced appetite, and are suitable for high-throughput screens used in drug development. 

NC3Rs-funded researchers are also developing quantitative measures of animals’ emotional state, both to support laboratory animal welfare and as refined approaches to research mood disorders. For example, a recent Project grant aims to understand how rats communicate their emotional state through ultrasonic vocalisations. We have also funded the development of a refined cognitive bias test which involves exposing animals to positive stimuli (a food reward) and a benign negative stimuli (a puff of air). The approach allows scientists to quantify the intensity of animals’ emotional responses and has been used in a number of studies to model mood disorders and understand the underlying mechanisms of treatment interventions. Building on this success, and with further funding from the Biotechnology and Biological Sciences Research Council, the group at the University of Bristol led by Professor Michael Mendl is developing a computer model of how emotion affects decision-making which aims to replace some animal use in research of emotional states and disorders. The group are also developing a home-cage version of the test, meaning rodents can participate in the task without the stress associated with being removed from their normal environment. 

The 2021 paper is part of an ongoing NC3Rs programme of work to refine the forced swim test to maximise the welfare of animals where it continues to be used, and replace the test with more quantitative and predictive approaches in research to better understand and treat depression. As part of this work, a position paper on the use of the forced swim test and its alternatives will be published shortly. 

Partial replacement includes the use of some animals that, based on current scientific thinking, are not considered capable of experiencing suffering. This includes invertebrates such as Drosophila, nematode worms and social amoebae, and immature forms of vertebrates such as fish. The Home Office issues licenses under the Animals (Scientific Procedures) Act 1986 (ASPA) for the use of protected animals in scientific research and testing in the UK. Under the Act, a ‘protected animal’ is 'any living vertebrate, other than man, and any living cephalopod'. Larval forms of fish and amphibians are protected animals under ASPA once they are capable of feeding independently. For zebrafish, this is five days after fertilisation. More information on the definition of the 3Rs can be found on our website.*