Depression is a mental illness that can manifest itself in numerous symptoms. Periods of sadness and negative thoughts lasting for weeks or months lead to dejection, avolition, and loss of interest, as well as to a variety of physical symptoms. These include insomnia, appetite disorders, and pain conditions. Depression can occur as an independent disorder or as a consequence of other serious underlying diseases or strains (1).

Bipolar depression occurs when a patient experiences periods of unfounded, excessively elevated mood (manic-depressive) in addition to symptoms of lassitude. In unipolar depression, on the other hand, manic phases don’t occur.

The underlying cause for depression is not known precisely. Factors such as a hereditarily increased risk, stressful, burdensome experiences or life circumstances including trauma, hormonal changes, physical illness, and lack of light can contribute to the development of the disease (2).

Depression is one of the most common forms of mental disorders worldwide. In Germany, around 8% of the population suffer from depression, with women being affected more frequently than men (3,4).

Depression in animals

Modern behavioural research attests intelligence and the capacity for emotions and suffering to animals. Animals can feel sadness, pain, fear, loneliness, and joy (5). If the negative moods are not only temporary, but last longer, a depression can be diagnosed also in animals. Aggression, anxiety, seclusion, or auto-mutilation are the most common indicators of a mental disorder. As in humans, the causes are manifold, examples being the loss of a partner, persistent stress, or illness (6).

Animal studies in depression research

There are many causes and factors involved in the development of depression in humans with the symptoms being very diverse and individually different. In animal experiments, however, only individual aspects already known in humans are taken into account in order to "produce", in turn, only individual symptoms of the disease in the animals. A feeling of worthlessness or even suicidal thoughts cannot be reproduced in animal experiments and are therefore - although they can be important features of depression - not even considered.

Since only single symptoms are artificially created in animal-based depression research, it is not surprising that there is not "THE 'animal model'" for depression, but tons of different ones. There are actually so many that only a selection of particularly frequently used ones and especially absurd and/or cruel methods are listed below (7-9). Mostly mice and rats are used for experiments, but other animal species such as monkeys and flies are also utilized.

• Loss of the ability to perceive pleasure (anhedonia) is a core symptom of depression. Rodents such as mice or rats usually like sweet foods. If they spurn an offered sucrose solution, this is defined as a sign of anhedonia. And if the interest in sucrose can be reawakened by test substances, these drugs are considered effective against depression.
• Similar experiments are also carried out with flies. For this purpose, they are locked in a plastic tube or a similar container, which is then shaken for several hours. After cutting off the wings, the animals are placed on a filter paper that is soaked with sweet glycerol in some places. No interest in the sweet liquid is interpreted as anhedonia. Thus, these flies are considered depressed. Drugs are then tested on the animals and the experiment is repeated (10).
• To create despair or lack of motivation in animals, various experimental setups are used. In the forced swimming test, a rat is placed in a Plexiglas cylinder filled with water. The rat swims until it realizes that it cannot escape; it gives up and drifts. If one rat drifts earlier than other rats, it is considered depressed. The "tail suspension test" is based on a similar principle. Mice or other rodents are suspended by their tails. Animals with high motivation try several times to free themselves. A lack of movement of the mouse is evaluated as passive/depressive behaviour.
• Depressed people often feel a loss of control when confronted with stressful events. This is replicated in the "learned helplessness model." One example of this model is rats being placed in a box whose grid floor is electrified for 60 seconds. The rats can stop the current - and thus the pain - by pressing a lever. This test is repeated several times. Rats that press the lever quickly are considered "unlearned helpless." Animals that do not press the lever, i.e., let the pain wash over them, are considered "learned helpless" and are used for depression research.
• Humans who experience social defeat show increased symptoms of depression, anxiety, social seclusion, and a loss of self-esteem. To replicate this in animals, male rodents in particular are placed with higher-ranking, aggressive rivals in their territory several times. After a few times, the inevitably ensuing subjugation of the inferior animal leads to decreased interactions, submissive behaviour, and anxiety, which is interpreted as depression.
• Depressed people often struggle with various anxieties. For this reason, particularly rodents are placed in experimental setups in which they encounter illuminated or free areas and darkened or enclosed areas. The observation might also take place in an unknown environment. The more the animals avoid the brightly lit or open areas, or the less actively they explore a new environment, the more fearful they are considered to be. If certain substances cause a prolongation of the stay in open/illuminated areas, they are said to have an antidepressant effect.
• In humans, withdrawal from stimulant substances produces symptoms that have strong behavioural and physiological parallels to depression. On this basis, there are studies in which animals are first addicted to amphetamine, cocaine, or alcohol for prolonged periods of time. The addiction is followed by withdrawal of the drugs and testing of antidepressants to resolve the symptoms.
• Early stressful experiences such as traumatic life events in childhood lead to increased sensitivity to the effects of stress later in life and influence individual susceptibility to depression. This observation in humans has been replicated in animal studies, primarily by separating newborn monkeys from their mothers immediately after birth and raising them in complete or partial social isolation.
• Depression can lead to a loss of the ability to discriminate odours. This is simulated by surgically removing the part of the brain responsible for the sense of smell from rodents. Affected animals are subsequently more irritable and aggressive towards conspecifics than non-operated rodents.
• Being exposed to stress over a long period of time can lead to depression or anxiety in humans. To simulate this chronic stress in animals, they are given high doses of cortisone for weeks to months or they are exposed to a series of unanticipated stressors for several weeks. These include deprivation of food and water for several hours, temperature reduction, tilting of the cage, exposure to flickering light, changes in the day/night rhythm, sitting together with alien (aggressive) conspecifics, frequent touching, and many examples more.
• By targeted breeding or modification of the genetic material, animals that are more likely to react with symptoms reminiscent of depression in the tests described above are "produced" to be used in those experiments.

Drugs to treat depression

The first so-called antidepressant "Imipramine" was launched in 1958 (11). According to Tom Bschor, a specialist in psychiatry and psychotherapy, antidepressants as well as actually almost all other psychotropic drugs were developed within a 10-year period in the middle of the 20th century (12). Since then, there have only been further developments and modifications (e.g., better tolerability of some drugs), but no improvement in efficacy (13). Thus, the list of antidepressants has grown significantly in recent years, but without any real innovations. In addition, all drugs used only relieve the symptoms more or less successfully, but do not offer a cure. Also, the mechanisms and processes by which the effects of antidepressants are achieved have not yet been clarified (12,14,15).

A major theory targeted by most antidepressants is that depression involves a deficiency of serotonin in the brain. Serotonin is a neurotransmitter that is important for communication among brain nerves. However, this theory, established as early as 1969, has been intensively challenged in many studies (16,17). Nevertheless, animal experiments continue to be carried out in this area and corresponding antidepressants are prescribed.

Therefore, it is not surprising that antidepressants don’t show a considerable effect. They help some patients, while others do not profit. Studies have shown that there was no significant improvement in quality of life or impact on the frequency of suicide attempts in patients taking medication compared with depressed patients receiving placebos (18-21).

Just like in animal experiments in general, there is a bias in public perception of the alleged benefits of antidepressants due to selective publications. The industry provided lots of money for medical studies, which leads to a bias in the publication of results. This is due to positive results being of particular interest for the industry out of financial reasons. Therefore, they are published more frequently than studies that do not provide evidence of efficacy. The result is a distortion of public perception, which significantly overestimates the effect of antidepressants (22,23).

Yet there is an extremely poor success rate, particularly in the development of psychotropic drugs, which includes antidepressants. 94% of psychotropic drugs that have been shown to be effective and safe in animal studies fail in the subsequent tests (clinical trials) in humans. The main reason is that they are not effective or cause high-grade side effects. Only cancer drugs fare worse, with a 95% failure rate (24).

Other treatment options

In addition to medication, there are a number of other therapies such as psychotherapy, light therapy, a therapy form of medically guided sleep deprivation for a short amount of time, repetitive magnetic stimulation, electroconvulsive therapy, and exercise therapy (25). Apart from psychotherapy, these have also mostly been developed and tested in animal studies (26-28).

Why "animal models" do not work in depression research

Even if animals can suffer from depression just like humans, there are good reasons why animal experiments in human depression research do not make sense, especially since no animals are used that naturally suffer from the disease. Depression is a very individual disease with many faces and a myriad of causes. Therefore, one can’t talk about THE depression or THE typical depressed patient. It is exactly this individual mix of symptoms and causes that is of great importance when it comes to the effectiveness of therapies. In animal studies, however, usually only individual symptoms of the disease are considered or artificially produced in so-called "animal models". Affected people will also wonder what rats or flies that spurn a sugar solution have in common with them and their disease. The same holds for rats that no longer fight back when they receive electric shocks or stop swimming in a container of water. The sense of such "animal models" is also doubted by many researchers, even those who themselves have done animal-experimental depression research (29-32).

Furthermore, the temporal aspect is completely disregarded. If not triggered by an acute incisive event, depression - like many other diseases – usually develops, over a long period of months and years. Animal studies, however, only take place during days or weeks.

The use of "animal models" for mental illnesses involves another important aspect beyond the normal problem of artificially creating individual symptoms. Is the behaviour of the animals caused by manipulation interpreted correctly at all? If rats subjected to the forced swimming test tend to drift, this is supposed to be a sign of hopelessness and thus depression. But is it not rather learned behaviour? The rat has realized that it cannot leave the water tank. It therefore saves its strength by letting itself drift (33,34).

A rat is considered depressed when it stops swimming.

The claim that such animal-based depression research is relevant to humans has already been questioned several times. In 2020, for example, a study investigated the extent to which findings from experiments with rats have been incorporated into subsequent human medical work. The result was that the studies with rats were primarily cited in other animal experiment-based publications. Only in less than 10% of cases, the papers were mentioned in human medical publications (35). In 2019, a study analyzed the relevance of experiments with monkeys to human medical papers on depression. Again, there was a finding that the animal experiments received little attention in subsequent human medical studies, but rather relied on findings from human-based in vitro ("in the test tube") or in silico (i.e., using computational methods) research approaches. Again, the animal-based experiments were cited primarily in other studies involving animals (36). This means that the current clinical understanding of depression is not based on research with animals.

Non-animal research methods

Population and patient studies

With mental illnesses such as depression, the problem cannot simply be broken down to an organ system, as is often done and possible with other illnesses. Therefore, population and patient studies with different foci are extremely important in order to gain knowledge about the causes of the disease or the effects of therapies. For this purpose, data from as large as possible a number of affected and healthy subjects is used.

Nowadays, there are countless possibilities for obtaining data. As complex and individual as depression is, so are the human-based research possibilities. Most of them are not or only slightly invasive, i.e. the measures do not involve any surgical interventions.  A blood sample is the most invasive measure in this area. However, it is precisely that blood sample which is a simple way to examine important data on the activation of certain genes, the level of inflammatory markers or of the stress hormone cortisone (37-40).

State-of-the-art technologies such as fMRI (functional Magnetic Resonance Imaging), fNIRS (functional Near-Infrared Spectroscopy), PET (Positron Emission Tomography), EEG (Electroencephalography), and MEG (Magnetoencephalography) can be used to measure brain activity and, in the case of fMRI, structural changes in the brain. In addition, psychophysiological measurements allow the analysis of the autonomic nervous system and the neuroendocrine system (41,42). If these examination methods are used, sometimes in conjunction with blood tests and computer programs, an enormous amount of important data can be obtained quickly. This is also evident in many patient studies that have been or are being done.

Through fMRI, brain activity and structural changes of the brain can be measured directly in humans.

An international consortium of scientists (IntegraMent Consortium), for example, is working on the genetic and molecular causes of depression (43). This work has already led to the discovery of new genes associated with severe forms of the disease (44). The BiDirect study is investigating the relationship between depression and arterial calcification before the occurrence of acute, clinical events, such as myocardial infarction (45). For the NAKO study, volunteers are being medically examined and questioned about their life circumstances to further explore chronic conditions such as depression (46). To study the dynamic processes in the brain during acute stress, the brains of healthy individuals and patients with depression or anxiety disorders were examined in a magnetic resonance imaging scanner while subjects were required to solve math tasks under time constraints. In addition, heart rate and cortisol levels in the blood were measured (37). To date, patients with depression have all been treated with the same regimen. The P4D study (Personalized, Predictive, Precise, and Preventive Medicine to Improve Early Detection, Diagnosis, Treatment, and Prevention of Depressive Disorders) aims to develop individualized treatment approaches using biomarkers, as well as magnetic resonance imaging, brain wave measurements, sleep diagnostics, and other tests (47).

In silico and In vitro methods

In addition to patient studies, various In silico or In vitro methods can provide insights into depression. One example is the recreation of a depressed brain in a computer model. Using this model, researchers found that prolonged depressive episodes can impair not only short-term but also long-term memory (48). In another study, neurons of the cerebral cortex were prepared from blood progenitor cells of patients and treated with the antidepressant Bupropion, which proved effective in only some of the patients. Based on a blood sample, biomarkers were identified that could be used to determine whether or not Bubropion is effective in a patient (49). A cell model was developed from human nerve progenitor cells. This model reflects the deleterious effects of stress on these cells and the amelioration of cell damage by treatment with the antidepressant Mirtazapine (50). Epidemiological and clinical studies suggest that ingestion of certain fatty acids may be effective in major depressive disorder. Using induced pluripotent stem cells from patients with depression, certain neurons were generated. Treatment of the cells with various fatty acids had a positive effect on the development of these neurons (51).

In another study, induced pluripotent stem cells from patients who respond either well or poorly to antidepressants of the Selective Serotonin Reuptake Inhibitor (SSRI) group were used to produce forebrain neurons. Evidence for the cause of this resistance to therapy was found in them (52,53).

Three-dimensional mini-brains (organoids), consisting of various brain-typical cells, are also being used in depression research. Various studies deal with the positive and negative effects of antidepressants or antidepressant substances on human brain organoids (54-56).

Prevention

The risk of developing depression in the first place can be significantly reduced by adopting a more mindful lifestyle. And even in patients with depression, the symptoms can be alleviated or the "good phases" can be prolonged. This is shown by various population and patient studies that have looked at the influence of exercise, diet, and addictive substances such as alcohol or smoking on the occurrence of depression (57-60).

Conclusion

Many diseases and especially mental illnesses such as depression cannot be broken down to generally valid individual symptoms. The development of depression is characterized by an individual and complex interaction between a highly developed human brain and a variety of external and internal factors. This must be taken into account in the search for the cause of the disease and its cure. "Animal models" with artificially induced symptoms can definitely not provide a solution. This is especially valid with regard to the fact that there is a huge variety of modern methods with which important patient data can be collected relatively easily. These must be used and developed further!

14 April 2023
Dr. med. vet. Gaby Neumann

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