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Critically evaluate the contribution that studies of animal models of depression

Introduction

Depression can be described as an emotional state characterised by extreme degrees of dejection and sadness. It is not a unidimensional disorder but includes manifold and multifaceted symptoms which are screened and assed by different models of depression, like for example animal models (Nowak et al. 1999). Depression is in the DSM-VI diagnostic system (American Psychiatric Association, 1994) defined by the presence of at least one core symptom (a) dysphoric mood or b) loss of interest or pleasure) combined with a number of additional subsidiary symptoms (e.g. feelings of worthlessness, suicidal ideation, loss of energy, decreased sex drive) for at least two weeks. As a matter of fact it has been discovered that specific symptoms of depression could be also found animals while others cannot be modelled in animals. Animals also exhibit certain to human depression similar behaviours and analogous biochemical configurations and alterations (Willner, 1990). As, nevertheless, animal models of depression were frequently criticised for having little relevance for the aetiology of depression and for having an unimportant impact on the understanding of depression in humans, the aim of this brief paper is to investigate whether animal models of depression have made significant contributions to today’s scientific understanding of depression in humans.

The number of existing animal models of depression has increased to currently more than 20 existing experimental models (Willner, 1990). Although they remarkably differ in terms of affecting disordered behaviour, most of them attempt to induce a reversion of behavioural abnormalities by using antidepressant drugs.
It has been said that before any model can be applied in clinical conditions it should exhibit acceptable degrees of face, predictive and construct validity. Face validity investigates if the phenomenological similarities between the model and the clinic are significantly positive whereas predictive validity estimates and compares the drug’s effectiveness in both experimental and clinical conditions (Bourin, 1990). Construct validity (see Vernon, 1963) is, according to Willner (1985), the most important validity indicator as it assesses whether the model possesses a strong theoretical rationale. This means for the validation of animal models of depression that they must exhibit “a change at the level of the construct being modelled is in fact central” to depression (Willner, 1985, p.120). In other words, some desirable features in a simulation of depression are that animal models should respond to antidepressant drugs; should employ realistic inducing conditions; and should model a core symptom of the disorder. In addition, for many purposes, such as investigating mechanisms of antidepressant action over a clinically relevant time scale, a prolonged time course is also desirable. Consequently, the clinical application of animal models would assume that it is possible to construct theories of psychopathology which are transferable from the nonhuman to the human species. However, most scientists argue that for most practical intentions animals’ subjective experiences are not accessible for experimental studies and as a consequence it is impossible to transfer subjective aspects of psychopathology from animals to humans. Nevertheless, it is widely accepted that the behavioural and cognitive experiences of abnormalities in animals can be simulated (Willner, 1985).

The Helplessness Model of Depression and other Animal Models

To assess the contribution animal models have made on the understanding of the causes, effects, and recovery methods from human depression it makes sense to start with the most influential model, namely, the so-called learned helplessness model of depression which has been examined more intense by scientists than any other animal model of depression (Willner, 1985).
Seligman and colleagues (e.g. 1969) discovered in the late 1960s that dogs who were subjected to experiments in which they received firstly uncontrollable shocks could later on hardly learn to avoid shocks in controllable situations but appeared to accept the shocks resignedly and passively. Dogs, who received at first controllable shocks, were, in turn, capable of learning to avoid shocks. Seligman (1975) explained this by proposing the learned helplessness model which states that when a member of a species learns that it has no control over negative events such as receiving electric shocks it will lead to a) motivation b) cognitive and c) emotional deficits in the particular member of a species. Succeeding studies revealed, in addition to that, organisms who feel helpless also exhibit decreased levels of appetite, lose weight and sleep, and have to endure physiological modifications in their neurotransmitter levels (Carson et al. 2000). Seligman and collaborators (1975) concluded that some types of human depression may underlie learned helplessness, after having discovered with his colleague Hiroto in 1975 that this model of learned helplessness was universally evident across organisms (including humans). Although this conclusion was far from revolutionary since, for instance, Bibring (1953) had already brought hopelessness and depression in significant connection to each other, it was for the first time that this hypothesis could be tested and supported with the help of the animal model of learned helplessness.
Abramson and collaborators (1976) improved Seligman’s model and demonstrated that pre-existing attributions (a) internal/external; b) global/specific; c) stable/unstable) decide over someone perceiving a situation as uncontrollable and giving in to depression or not. However today a revised so-called hopelessness theory of depression (Abramson et al. 1989) is tested which states that a state of hopelessness had to be felt before depression could be triggered in someone by pessimistic attributions and one or several experienced negative life events.

Consequently, one can state that the promoted clinical role of a perception of helplessness in the causation of depression has experienced many complex modifications so that the animal model’s direct implication for humans has been questioned (Abramson et al., 1989). In fact, retrospectively speaking the learned helplessness paradigm is now only of historical interest as it only had a significant influence on clinical thinking but not clinical applications. It has also been found that the reason for rodents to give up is not due to cognitive learning deficits but rather due to the fact that increased stress decreases attention and thus leads to distraction which makes it impossible for rodents to seek and learn solutions in controllable stressful situations after having experienced uncontrollable stressful situations (Willner, 1991).
Willner (1991) maintains that despite these facts helplessness studies are crucial in examining the observed but hardly ever explained practical correlates of the abnormalities of noradrenergic transmission in depressed patients. The many analogous symptoms to sever depression is another strength of this animal model which is manifested by the fact that the American Psychological Associations (1980) criteria for major depression seem to have been met by rodents who experience uncontrollable stress situations (see Weiss et al, 1982).

This led to selective breeding programmes which intended to result in creating strains of rodents that had physiological and behavioural conditions and configurations similar and analogous to depressed individuals. The Flinders sensitive line (FSL) of rats, which were bred to their sensitivity to a cholinergic agonist, show abnormalities, relative to outbred strains, in a number of behavioural tests; these include an animal model of depression, the behavioural despair model (Porsolt forced swim test), which is of relatively low validity as a simulation of depression (Willner, 1984) but is used routinely in antidepressant screening (Borsini and Meli, 1988).

A model which is very closely linked to the helplessness model is the behavioural despair (or swimming test) model (Overstreet, 1988). This model was developed with the help of experiments in which rats or mice were forced to swim in a place with no escape possibilities. After desperate initial attempts to escape the animals gave in to their destiny and rested in a static state called behavioural despair (Porsolt, 1981). Different antidepressants were used to investigate how this state of behavioural despair can be overcome. Overstreet and Measday (1985) found in studies using the Flinders sensitive line (FSL: rodents bred to their sensitivity to a cholinergic agonist) that imipramine reversed a avoidance learning deficit in these animals. Consequently, these kinds of studies represent an interesting attempt to utilise an animal model of depression to find support for clinical hypothesis (Willner, 1991).
However, the behavioural despair model itself was heavily criticised and many rejected its implications for the treatment of depression in humans since it was discovered that some drugs which were already found to successfully decrease depression did not have any effect on rats’ behavioural despair state whereas, on the other hand, more remarkably, some non-antidepressants were found to effectively change the immobile posture of the swimming animals and helped them overcome the feeling of helplessness (Willner, 1985). The extent to which the behavioural despair model helps understanding the aetiology of depression in humans consists of the discovery that the despair behaviour demonstrates different degrees of stress and depression can be therefore described as being partly influenced by individuals’ genetic make-up.

As a matter of fact, many scientists (e.g. Howard et al. 1981) regard separation models of depression as the models which can be usefully transferred to humans.
Separation experiments include the separation of mostly non-human primates from their mothers who as a result demonstrate protestant behaviour which can be identified by screaming, sleeplessness and aggressiveness but which leads to despair symptoms of low activity, play, social interaction, and appetite after a few days. These two sequential forms of responses, in turn, are very similar to anaclitic depression (see Spitz, 1946) which is exhibited by separated children. Hence, the animal models of separation led researchers to the assumption that separation from the close social network can result in adult depression but since to date it could not be decided whether separation precipitates depression in humans or conversely, even this animal model could not offer significant implications for human depression (Willner, 1985).

In general, human studies have been used to explain animal models of depression and not the other way round which would have been more desirable. Additionally with the exception of the mentioned utilisation of animal models to screen antidepressant drugs their contribution to improve the treatment of depressed individuals is less than convincing. One of the only implications gained from animal studies is that supportive social situations may have a positive effect on depression therapies and serve as a protection from stress and depression. This has been proposed by Suomi (1976) who discovered that monkeys who are allowed to play with peers after having been isolated from their social network recover faster from depressive moods. Dorish and collaborators (1989) reported, additionally, that animals who live in groups perceived significantly less amounts of stress than single animals. In a similar vein, Willner (1991) maintained that only recently studies have discovered sex differences in degrees of susceptibility to depression in humans. It was found that unipolar depressions are up to three times less prevalent in men than in women and Kennet and colleagues (1986) discovered congruently, that male rats were more likely than females to cope with behavioural despair and uncontrollable shock and stress and suffered less from anhedonia (a decrease in fun and pleasure)

Chronic mild stress (CMS) procedures were devised to examine more closely this particular symptom of depression which is also defined by the DSM-VI as the melancholic subtype symptom of major depression (American Psychiatric Association 1994). Mild stressors are chronically and sequentially which are offered to rodents lead to them being less enthusiastic and responsiveness to rewards which is usually assessed by a maximised consumption for sucrose over water or by the reduction in the preference of dilute sucrose solutions. This over weeks sustained mild stress causes not only anhedonia but also has a negative impact on sexual drive, locomotor actions, sleeping behaviour which are all DSM-VI recognised symptoms for depression (Willner et al., 1998). Additionally, this model of animal depression succeeds at showing that anhedonia and minimised sensitisation to rewards can be reversed by both antidepressant drugs and by ECT (electroconvulsive therapy) but leaves unaffected if treated by non-antidepressants (Papp et al., 1996).

Conclusion

On the one hand, there are models based on stress such as the learned helplessness model, the forced swimming test and the chronic mild stress model and, on the other hand, models based on neuronal deficits such as the olfactory bulbectomy model. Although these animal models of depression are in current use (reviewed by Willner 1990), most of them have some pivotal limitations, such as, a short time span, the use of extremely unethical and extreme situations and conditions (e.g. electric shocks, cruel swim experiments). Additionally, to date, among models more frequently used in depression, none of them meet all criteria for validity (face, predictive, construct).
Additionally, it has been proven difficult for researchers to transfer animal experiments to real world settings which remains a challenge for scientists engaging in this particular area of research. Despite their lack of validity, animal models are to date the most optimal tool for both examining and identifying potential effects of antidepressant drugs; and thus represent the best way to study their mechanisms of action. As a matter of fact, some models (e.g. CMS model) were able to sufficiently demonstrate some symptoms of depression in animals which also are evident in humans and it will remain an intriguing task to identify the implications which these findings can have for the understanding, aetiology and treatment of depression in humans (Willner, 1991).

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