Pressure grows to ditch controversial forced swim test in rodent studies of depression

Scientists are searching for more precise ways to gauge the effects of psychiatric drugs on animals

For the past few decades, scientists studying candidate antidepressant drugs have had a convenient animal test: how long a rodent dropped in water keeps swimming. Invented in 1977, the forced swim test (FST) hinged on the idea that a depressed animal would give up quickly. It seemed to work: Antidepressants and electroconvulsive therapy often made the animal try harder. The test remains popular, appearing in about 600 papers per year.

But researchers have recently begun to question the assumption that the test really gauges depression and is a good predictor of human responses to drugs. Opposition to the test is snowballing, driven in part by concerns it is unnecessarily cruel given its spotty results. This month, following similar moves by the Australian government, the United Kingdom’s Home Office announced it would require U.K. researchers to justify the use of the test and would encourage other U.K. ministries that regulate animal research to “completely eliminate” it.

Such changes add urgency to efforts to develop better animal tests of psychiatric drugs’ effects. Neurobiologist Anne Mallien of Heidelberg University, who studies the effects of the FST on rodents’ well-being, says she would love to have other options. “The thing is that alternatives are somewhat missing.”

In the FST, researchers put a mouse or rat in a container of water, usually for about 5 minutes, and time how long it exerts itself before giving up and simply floating. Rodents will often swim longer when treated with psychiatric drugs. “But does that mean something for [human medicine]?” says neuroscientist Carole Morel at the Icahn School of Medicine at Mount Sinai. The rodents’ high stress levels could complicate the results, and an intelligent animal quickly learns that researchers will rescue it once it gives up.

Those limitations soured some researchers on the test, and animal rights activists including People for the Ethical Treatment of Animals (PETA) have added to the opposition. “It’s a waste of time,” says Emily Trunnell, PETA’s director of science advancement and outreach. “These are mice whose lives are very different from humans who experience depression.”

In December 2023, Australia’s National Health and Medical Research Council said it will no longer fund most research using the FST because the test’s impact on animals “cannot be justified.” Meanwhile, the Australian state of New South Wales made the FST entirely illegal in December. And at least 13 major pharmaceutical companies have said they no longer use the FST in psychiatric drug testing. The U.S. National Institute of Mental Health (NIMH) has discouraged use of the FST but not banned it outright.

Researchers are now searching for newer tests that measure specific behaviors associated with mental health, such as enjoyment of life, healthy sleep patterns, or resiliency to stress. The trend is in line with the idea that “depression” in humans may not be a single disorder, but rather a diverse collection of neurological traits. NIMH published a statement in 2019 urging researchers not to design animal behavioral tests around specific clinical conditions such as depression, or invoke those conditions to describe their results. Still, a recent analysis found 60% of papers published between 2018 and 2020 described animals in the FST as showing “depression-like behavior.”

The FST is good for studying stress, but “as a tool to discriminate antidepressants, it really raises a lot of eyebrows,” says pharmacologist Marco Bortolato of the University of Utah, who is developing rodent tests for behaviors linked to mental illness. In a 23 February paper in Neuropsychopharmacology, he presented a new test that may discriminate drugs more accurately—at least when it comes to their effects on persistence or “grit.”

In the test, a mouse learns it can get out of a water tank by climbing onto one of several platforms, but then finds that they sink when it steps onto them. Researchers measure how long it keeps searching for a stable platform before abandoning the strategy. The team found that giving the mice the antidepressant fluoxetine or having them exercise increased their persistence, and mice who gave up easily had gene activity in their brains associated with susceptibility to chronic stress.

“It sounds quite promising,” Mallien says of the sinking platform test. She notes the test uses warm water, which helps minimize stress on the animals.

Another strategy is to combine animal tests already in use to measure individual symptoms. “Probably not one single mouse model nor one single test can really reflect a human disease condition,” says neurobiologist Moritz Rossner at the Ludwig Maximilian University of Munich. His group has developed a partially automated system called PsyCoP that uses transponders implanted in the animals’ necks, along with cameras and sensors in their cages, to monitor mice as they perform 11 behavioral tests. These address characteristics including enjoyment of life (measured by the mouse’s consumption of sugar water) and social defeat (measured as resilience after being bullied by a bigger mouse).

In an unpublished study, Rossner’s team used its system to test lithium, a standard bipolar disorder treatment, in mice genetically altered to mimic that condition. Treated animals did better on cognitive tasks thought to be impaired in bipolar disorder in humans. But the drug didn’t affect their circadian rhythms, which are disrupted in humans. Rossner says the result points to the danger of relying too heavily on a single test. If they had only tested circadian rhythms, Rossner says, “we would have been very disappointed”— and wouldn’t have learned anything new.

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