In 2022, more than 22 million Americans had serious thoughts of suicide or had made a plan to end their life. To treat depression, the leading cause of suicide death, there is an urgent need for novel antidepressants, as existing ones are only effective roughly 50% of the time. But there is a serious problem with the way we conduct research to improve depression treatment. An upcoming advisory council meeting might offer an opportunity to finally change it.
When I started my psychiatry training in 1996, I read a lot about the forced swim test (FST) as a model for depression. Developed in 1977 and purported to produce depression in mice, the procedure requires that a mouse be placed in a small tank filled with water from which escape is impossible. The mouse initially struggles to escape, but as exhaustion sets in, it proceeds to immobile floating, which is presumed to represent a depressive state.
The tail suspension test (TST), a sibling of the FST, was developed in 1985 and requires that a mouse be suspended by its tail in a small chamber so that it can neither escape nor hold on to a nearby surface. As in the FST, when the mouse becomes immobile, no longer struggling to get free, it is considered to be in a “depressed state.”
The theory was that these mice could be used to screen antidepressants for their effectiveness, but the results have been mixed at best. While some known antidepressants increase the amount of time mice spend struggling to escape, which ostensibly suggests the meds are staving off depression, the tests don’t reliably predict the effects of promising new drugs such as ketamine — or even of an older drug such as Prozac. Is the immobile mouse a stand-in for sadness, emptiness, hopelessness, tearfulness, worthlessness, guilt, self-reproach, cognitive difficulty, or thoughts of death or suicide in the human? Anyone who has ever experienced depression knows intuitively that the answer is decidedly no.
What have we learned about the FST and TST since 1977? They are not models for depression or despair at all but rather “an enormous anthropomorphic leap.” In response to criticism, proponents of the tests shifted from calling them models of depression to models of “depression-like” behavior. However, not only is immobility not analogous to human depression, but it is now understood as more likely to be an adaptive stress-coping strategy.
The FST has not been considered valid for at least 15 years. It does not replicate depression, it produces numerous false positives and false negatives, and it has failed to result in new antidepressants after 47 years. Accordingly, the United Kingdom and Australia have moved to prohibit the test. In 2019, Joshua Gordon, then director of the National Institute of Mental Health (NIMH), noted that “traditional behavioral responses to stress paradigms are particularly problematic,” adding that tests like the FST and TST have largely failed to predict neural mechanisms of human psychiatric illness or drug responses.
And yet the National Institutes of Health (NIH, of which NIMH is one institute) continues to fund studies using the FST, and researchers continue to publish papers making depressive-like behavior claims. While the publication rate for FST studies was 10-15 per year in 1985, it rose to 300-400 per year in 2015 and 600 per year by 2021. Over 90% of behavioral neuroscience results fail to translate to humans, and over 92% of psychiatric drugs in development fail in human clinical trials, despite safe and effective findings in nonclinical animal tests.
Human depression is a widespread, debilitating, and sometimes fatal illness. Research funds are scarce, and the government has a responsibility to spend those funds wisely, with an eye to alleviating the scourge of depression in sufferers. Meanwhile, principles of animal research ethics necessitate that researchers consider whether no alternative method is available, what the expected net benefit is, and if there is sufficient value to justify harm. The FST and TST do not satisfy these requirements. We now have multiple powerful research methods available for modeling neuropsychiatric diseases in humans, including 3D cell models, imaging, and bioinformatics. Earlier this year, NIH Director Monica Bertagnolli signaled a major shift due to technological advances in non-animal-based approaches, indicating that the NIH will prioritize the development and use of these methods to more accurately model human biology, including the biology of psychiatric disorders.
It is high time for researchers to retire the forced swim and tail suspension tests. On Tuesday, the National Advisory Mental Health Council (NAMHC) — which advises the director of the NIMH (currently Acting Director Shelli Avenevoli) — will hold an open policy session. Let’s urge the NAMHC to tell NIMH: Stop spending taxpayer dollars on obsolete tests that needlessly harm animals and leave patients in the lurch by diverting research funds to bad science.
If you or someone you know may be considering suicide, contact the 988 Suicide & Crisis Lifeline: call or text 988 or chat 988lifeline.org. For TTY users: Use your preferred relay service or dial 711 then 988.
Karen S. Greenberg, M.D., is a psychiatrist affiliated with the Beth Israel Deaconess Medical Center and instructor, part-time, at Harvard Medical School. She is also an alumna of the Harvard Medical School Center for Bioethics fellowship.
