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Unraveling Decades of Flawed Depression Research

Written by Kati Bertrand
October 2025

Grey mouse closeup© iStock.com/Pakhnyushchyy

What Is Depression?

Depression can refer to a specific diagnosis, such as major depressive disorder (MDD), or as a component of complex medical conditions, such as the depressive episodes seen in bipolar disorder. Other medical conditions associated with depression include seasonal affective disorder, postpartum depression, and premenstrual dysphoric disorder. Each of these has distinct causes, symptoms, and treatment options.

Depressive disorders are the leading cause of disability worldwide, affecting approximately 280 million people.1 Yet after decades of cruel experiments on animals, little has changed in terms of treatment. In fact, almost 95% of biomedical interventions for depression that looked promising in animals ultimately fail in human trials.2 This sobering statistic underscores fundamental species differences: mice, rats, monkeys, and humans diverged long ago, each evolving their own unique brain chemistry, immune response, and genetics.3

According to the American Psychiatric Association’s fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR), a patient with major depressive disorder must express at least five of nine symptoms for at least two weeks;4 it’s not unreasonable to require similar criteria for experiments that are supposed to mimic human depression. A 2020 paper pointed out that “even if the bar for a diagnosis in animals is lowered as much as possible — by ignoring important details of each feature that psychiatrists would look for in humans (e.g. its duration) — it is clear that no experimental intervention (e.g. drug treatment, genetic alteration, neuronal lesion) has yet produced a collection of abnormalities in animals that would qualify as a ‘model’ of depression in terms of its symptom profile, let alone its severity and temporal instability.”5

Consequently, the animals used in these experiments do not capture key human features of the disease. Meanwhile, contemporary pharmacotherapy primarily manages symptoms, forcing patients and prescribers into a tedious trial-and-error approach that often fails to achieve lasting remission.6

Animal Models of Major Depressive Disorder

Distress Framed as Data

Attempts to model human depression in animals typically focus on one aspect of the condition (e.g., anhedonia or stress response), but this oversimplification is problematic as it assumes that forcing animals to endure stressful manipulations will recapitulate human experiences, and it neglects subjective, reportable factors like perception, personality, and culture.

In the forced swim test (FST), experimenters put mice, rats, guinea pigs, hamsters, or gerbils in inescapable containers filled with water. The panicked animals try to escape by attempting to climb up the sides of the beakers or even diving underwater in search of an exit. They paddle furiously, desperately trying to keep their heads above water. Eventually, they’ll start to float.

Immobility or floating was originally interpreted as “despair,”7 but most experts now disagree with this interpretation.8 Floating more likely reflects an adaptation to acute stress, which is biologically and psychologically distinct from the complex, chronic state of human MDD, or an energy-conserving mechanism adopted when escape is impossible.9,10 This lack of specificity adds to the test’s unreliability in identifying effective, targeted treatments for depression.

This notorious unreliability has been well documented in recent years. U.K. scientists and drug regulators have advised companies against using the FST to test efficacy of potential new antidepressant drugs (ADs), warning that “if excessive reliance is placed on the FST as a gatekeeper for clinical development, then the existence of potentially effective ADs that are inactive in the test will remain unknown.”11 The U.S. Food and Drug Administration confirmed to STAT that it doesn’t require the FST,12 and regulators and government officials in the European Union13 and New Zealand14 have criticized it. In a study published in Drug Discovery Today, SAO Director Dr. Emily Trunnell discovered that the use of the test by major pharmaceutical companies did not result in any new, marketable therapeutics to treat depression.15 A series of citation analyses discovered that authors who study MDD in humans rarely cite results from experiments on animals and instead preferred to reference research using human cells and human data.16,17,18

The tail suspension test (TST) is similarly used in crude attempts to measure depression or test antidepressant drugs. In the TST, experimenters suspend mice upside down and tape their sensitive tails to a horizontal bar. The animals struggle to right themselves, feeling distressed by their awkward position and lack of control. Trying their hardest, they attempt to pull their bodies up, holding on for dear life to the tape affixed to their tails—only to drop back down again and resume their exertion. Both the FST and TST are considered highly contentious and severe due to the significant distress they induce.19 Furthermore, results can be easily distorted by variables such as the animal’s age, weight, strain, or specific handling protocols.20

Creating Trauma, Calling It Depression

Even worse, experimenters frequently attempt to purposefully induce depression in animals. Chronic unpredictable “mild” stress (CUMS) paradigms subject animals to uncontrollable pain through electric shocks or chronic stressors such as restraining them for extended periods of time, denying them water and/or food, tilting their cages, forcing them to live in wet bedding, shaking them, or disrupting their circadian rhythms. Animals are often made to live in complete isolation from other members of their species. It is hard to comprehend how any of these types of stressors could be regarded as “mild,” especially when considering the cumulative harm.3

In chronic social defeat stress (CSDS) experiments, a vulnerable mouse is forced into a cage with a larger, more aggressive “resident” mouse, who will often violently attack the less aggressive “intruder.” These animals are bullied and physically assaulted by other animals in an effort to induce a depressed or altered mental state. A 2022 review pointed out that “the stress in CSDS is more severe than one commonly experienced by humans”21 and that this model “is not applicable to females.”

While these experimental paradigms can induce symptoms like anhedonia, key diagnostic criteria of most neuropsychiatric disorders are subjective and cannot be evaluated in animals at all. Cognitive deficits, excessive guilt, and suicidal thoughts have no clear animal equivalent.

“Learned helplessness” is a state that experimenters have often achieved by shocking animals so frequently and unpredictably that they stop trying to escape the shocks. Psychologist Dr. Kathryn Hahner wrote: “Seligman and colleagues linked learned helplessness in animals to clinical depression in people with a series of questionable assumptions.”22 The name implies that prolonged stress induces a state of mind in the animal that is somehow comparable to the feeling of helplessness experienced by depressed humans, but the majority of researchers acknowledge that this theory got it backward—the escape deficit arises from passivity, rather than “depression,” which is triggered by a lack of control over environmental stressors.23

In maternal separation experiments, newborn and infant animals are taken from their mothers for extended periods of time—sometimes indefinitely—in attempts to induce depression. However, the model’s weaknesses include inconsistent outcomes, methodological variations, and questions about its translational relevance to human depression. These include differences in stress exposure due to separation length and animal strain, which can lead to unreliable results, as well as the fact that the model does not replicate most human early-life adversity or its long-term effects.2

Not only do these cruel tests lack applicability to humans experiencing depression, but they also cause animals to suffer immensely —a serious ethical concern in its own right. In addition, the severe stress that the animals endure affects every physiological system in their bodies, introducing confounding variables that are often overlooked in data interpretation.

Brain Damage as Behavioral Proxy

Surgically removing the olfactory bulbs (olfactory bulbectomy or OBX) causes a wide range of abnormalities, some of which experimenters pass off as a depressive state. However, a major confound of this model is that OBX animals are hyperactive, at odds with the hypoactivity common in depressed humans. Also, depression in humans does not typically require such severe surgical intervention. Even though this model has been considered a “gold standard,” there is no evidence that it “has been responsible for the discovery of even a single novel antidepressant currently in clinical use” and “screens for new and fast-acting antidepressants using the model have produced false positive and negative results.”24

Genetics, Drugs, and Misread Behaviors

Genetic models, which involve gene deletion or selective breeding, are used in an effort to mimic the specific biological basis of human depression. For example, Flinders Sensitive Line rats are selected for depression-like behavioral traits such as decreased activity and anhedonia.25 Still, “[i]nterspecies differences remain a critical barrier, given the substantial variation in brain anatomy, neural circuitry, developmental trajectories, and gene regulatory mechanisms between mice and humans.”26

Injecting mice with reserpine was one of the first ways that experimenters attempted to model depression in animals. The drug was used to treat hypertension until the early 1960s, when it became associated with suicidal depression (though there’s now evidence which contradicts this).27 Reserpine’s supposed depressive effects were a foundation for the monoamine hypothesis of depression (a theory that is now debunked) and, given that it causes additional effects such as hypothermia and hypotension, which are not seen in human patients, it is less frequently used.3

The loss of a rodent’s natural preference for sweet fluids (measured by conducting the sucrose preference test) after facing a prolonged series of stressors is often interpreted as a sign of ‘anhedonia,’ which is a prominent element of depression in humans. However, the diagnostic criteria for anhedonia in humans “is ‘a markedly diminished interest or pleasure in many, or all, activities, nearly every day’ — that is, the anhedonia is not confined to a gustatory preference.”4 Similarly, experimenters often label an animal’s submissive or passive responses following stressors like social defeat as “depression-like” behavior, without ever describing what “depression-like” actually means or which aspects of depression it is supposed to mimic. Though anhedonia, passivity, and the appearance of lower self-confidence could occur in animals following social defeat experiments, in humans, these symptoms are “not normally attributed to threats of physical attack from a dominant conspecific.”3

Experiments on animals that attempt to model depression sub-types

Animal Models of Treatment-Resistant Depression (TRD)

About one-third of depressed patients are “treatment-resistant,” meaning their symptoms persist despite multiple trials with standard antidepressant therapies. Researchers have attempted to model TRD by administering substances or introducing factors that increase inflammation and, in theory, make antidepressants much less likely to produce positive effects, for example, interleukin 6,28 chronic adrenocorticotropic hormone,29 lipopolysaccharide,29 feeding them a high-fat diet,30 and/or using certain genetically modified strains. But these models are also limited by all the previously mentioned flaws of animal experiments in general, flaws that “hamper our capabilities to investigate treatment-resistant depression.”31 In other words, if basic models can’t even fully mimic “simple” depression, they are most likely unreliable for its most stubborn form.

Animal Models of Bipolar Disorder

Bipolar disorder, with its characteristic manic-depressive cycles, is even less appropriate for animal use. Manic episodes in humans involve grandiosity, hyperthymia, and sometimes psychosis, while depression swings into low mood and lethargy. No animal can capture the spontaneous oscillation between these complex states. Experts state that “animal models of bipolar disorder do not exist” because mimicking the alternating cycle is impossible.32 Unsurprisingly, these types of experiments have failed to meaningfully contribute to clinical knowledge or advancements for bipolar depression.

Implications and the Path Forward

Decades of depression experiments on animals have failed to bring the new, more effective drugs they’ve promised. Despite this, thousands of published papers ignore these results, and experimenters continue to use animals to draw flawed conclusions. Clinical trial failures for novel therapeutics provide crucial evidence of this translational failure. For example, a recent Johnson & Johnson drug candidate, expected to reduce dysphoria based on rationale from animal experiments,33 was shelved for depression development due to low efficacy in phase 3 trials.34 Adding insult to (psychological) injury, reproducibility of these experiments is notoriously low because environmental factors, like housing, even ambient noise or handling, can dramatically alter outcomes.35

Scientists and drug evaluators must move beyond outdated animal assays.

Overall, experiments on animals have been cited as the primary source of drug failure in human neurobehavioral trials.36 A primary reason for this is because even though animals feel many of the same emotions we do, their brains are fundamentally different in ways that are critically important in biomedical and molecular research. For example, the brain cells that respond to drugs meant to treat depression, anxiety, and bipolar disorder are different between mice and humans.37

The limitations of animal models force an urgent shift toward human-relevant, non-animal models. This shift is supported by regulatory changes, such as the U.S. Food and Drug Administration’s recent policy shift toward accepting non-animal alternatives for investigational new drug applications, an acknowledgement that “the high and rising attrition rates in pharmaceutical R&D demand immediate action.”38

Human induced pluripotent stem cell (hiPSC) technology offers a path toward precision psychiatry by enabling scientists to reprogram adult human somatic cells into neural cells, creating patient-specific disease models in vitro.39 Advanced tools, including artificial intelligence and the analysis of extensive human ‘omics data (gene transcripts, epigenomes), are being used to identify molecular targets and predict treatment response in human populations.40 For example, scientists at the Johns Hopkins Center for Alternatives to Animal Testing have used stem cell–derived “mini-brains” to study the effects of an antidepressant drug on neurons in the developing human brain.41 These human-based approaches must take center stage if we hope to develop genuine cures for depression. As one review warns, the established animal paradigm “has failed to lead to the development of new treatments and the biological mechanisms of depression are still poorly understood.”29

As Dr. Trunnell has written, “[p]ublic acceptance for experiments involving animals is predicated on the assumption that animals are used only when absolutely necessary, when their use is expected to benefit humans or other animals,”42 but the history of depression research has been written in the language of animal suffering and human disappointment. The future doesn’t have to follow this path. Every grant, every study, and every patient waiting for effective cures should push science toward models that truly reflect the human experience they’re meant to help. With the emergence of powerful human-based technologies, we now have the tools to reshape the future and replace obsolete experiments on animals with compassionate, cutting-edge science that finally delivers real hope to those who need it most.

  1. World Health Organization. Depressive disorder (depression). WHO.int. August 29, 2025. Accessed October 21, 2025. https://www.who.int/news-room/fact-sheets/detail/depression
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  13. Committee for Medicinal Products for Human Use (CHMP). Assessment Report: Spravato. International Non-Proprietary Name: Esketamine.; 2019. https://www.ema.europa.eu/en/documents/assessment-report/spravato-epar-public-assessment-report_en.pdf
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