For decades, scientists have used the mouse forced swim test to study depression. Now some are reconsidering it

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Testing mice for depression is challenging.

“You can’t put a mouse on a psychiatrist’s couch and ask it how it’s feeling,” said Sarah Bailey, who heads the pharmacology group at the University of Bath in the U.K. 

Bailey looks for new drugs that can treat depression. Her work involves experiments with mice, which means she has to study them for depression. 

She uses a standard experiment called the forced swim test. Researchers put mice in a tank of water for a few minutes. The mice float, but do not like being in water, so they swim to get out. 

After a while, the mice give up, and float. 

“In my experience using the forced swim test, no mouse or rat has ever drowned,” Bailey said. “These mice are naturally buoyant when they’re immobile.” 

Then the researchers take the mice out, dry them off, put them in a temporary cage on a warm mat, and then return them to cages with other mice. 

Scientists in the 1970s found that mice will swim for longer if they get an antidepressant. Thus, a new unknown drug that makes mice swim for longer during this test could have potential as a new antidepressant. 

Since then, the forced swim test  has become a standard experiment  for antidepressants, including for the development of well-known drugs like Prozac and Zoloft. But now, some researchers and government agencies question how useful the test is for research in the future and its impact on animals. 

Australia’s National Health and Medical Research Council said they will no longer fund most research using the forced swim test. The National Institute of Mental Health in the U.S. discourages researchers from using it. The U.K. government said they will look at research proposals that use this test more closely, to see if there are other ways to do the work. 

Bailey said scientists use other tests as well, but there is nothing like the forced swim test. 

“As yet, there are no alternatives to using the forced swim test,” she said. “It remains the most well validated test of antidepressant efficacy.” 

However, some scientists have moved away from the test in recent years, like Scott Russo, a neuroscientist at the Icahn School of Medicine at Mount Sinai in New York. 

He used to use the forced swim test to study stress and depression in mice, but started phasing it out around eight years ago. 

“There hasn’t been a huge loss in the type of knowledge that we gain from not performing the forced swim test anymore,” he said. “It was never really clear how relevant it was to human depression and its ability to identify new potential antidepressants is incredibly limiting.”

For one thing, he said that mice respond to antidepressants in minutes or hours, whereas humans can take weeks before antidepressants start working. 

He added that it’s not clear if the forced swim test will be useful for discovering drugs that can work as antidepressants in new ways, like ketamine. 

Kathrin Herrmann, a veterinarian at the Center for Alternatives to Animal Testing at the Johns Hopkins Bloomberg School of Public Health, welcomes a move away from the forced swim test.

Three years ago, she found researchers studying major depressive disorder in humans rarely cite research done using the forced swim test. 

“Obviously if something is translatable, if it’s useful for the clinic, clinicians would cite that in their papers,” she said. “So that’s a big red flag.” 

As an alternative to the forced swim test, pharmacologist Marco Bortolato at the University of Florida has proposed the sinking platform test. He said mice in the forced swim test fear they will drown — so besides depression — they could be feeling fear, anxiety, or other emotions. 

“There are many additional components that we consider as potential confounds,” he said. 

He suggested a more targeted approach to test for persistence — how often a mouse will try something, without the fear of dying. 

In the sinking platform test: researchers put a mouse in a tank of water, but it can climb on platforms to escape. Some platforms will sink. Once that happens, there will be more platforms to climb. 

“So in essence, the animal learns that this escape strategy … can sometimes occasionally fail.” 

After a few days, the mouse will do this test in a set up where all the platforms sink, so the researchers can count how many platforms a mouse will climb on before it gives up. 

Bortolato said a chronically stressed mouse climbs fewer platforms, whereas a mouse treated with antidepressants climbs more platforms. He said his team has tested two antidepressants, but it will take years of work before this, or any other test, can become a new standard. 

Pharmacologist Sarah Bailey, who still uses the forced swim test, said she will need to see more data on the sinking platform test to consider it as a viable alternative. However, she added that the forced swim test is a single, 6-minute test that mice can recover from, whereas the sinking platform test requires days of training. Her concern is that researchers would “end up using more animals in tests that are less well-validated in order to try to draw the same conclusions.”