Are Animal Models Relevant in Modern Psychiatry?

The use of animals in medical research became firmly established in 1865, with the publication of An Introduction to the Study of Experimental Medicine by Claude Bernard.¹ This scientific discourse laid the groundwork for the study of comparative physiology between animals and humans. Half a century later, the animal model was introduced into the behavioral sciences by early theorists Pavlov (classical conditioning), Watson (behaviorism), and Skinner (operant conditioning). Later, the animal model was used to investigate conditions ranging from maternal deprivation to depression and learned helplessness.

Most early psychiatric drugs were discovered through serendipity rather than through the use of animal models. Isoniazid, originally used to treat tuberculosis, was found to possess mood-altering properties and was marketed as the first antidepressant in 1957.^2,3 MAO inhibitors originated from an effort to develop antituberculosis medications; they were superseded by tricyclic antidepressants (TCAs), which were discovered by clinical observation.

The potential psychotropic effect of chlorpromazine, originally used as an anesthetic adjunct in a Paris hospital in 1952, was discovered by a military surgeon later in the same year.^4,5 Thus, the phenothiazines came from a search for better pre-anesthetic agents.

The Australian physician John Cade⁶ reported the calming effect of lithium in humans in 1949. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally in 1955.⁷ The first studies of benzodiazepines were unsuccessful attempts to treat patients with schizophrenia.⁸

In contrast to discoveries made through chance observation, newer psychotropic drugs, such as SSRIs, were discovered through the process of rational drug design. Five SSRIs (citalopram, fluvoxamine, fluoxetine, paroxetine, sertraline) were produced independently by 5 different companies.⁹ Rational drug design remains the main driving force behind the development of modern psychiatric drugs.

Animals as model systems in psychiatry

Since the mid-20th century, researchers have designed animal models of stress, anxiety, depression, and obsessive-compulsive conditions in the laboratory to develop, test, and validate drugs to treat human disorders.^10-13 Rats and mice are most commonly used in specific behavioral tests, such as the despair test, tail suspension test, and open field test.

Current animal models of human psychiatric conditions face the same methodological limitations as they did 30 years ago. According to Beach¹⁴:

The validity of interspecific generalization can never exceed the reliability of intraspecific analysis; and the latter is an indispensable antecedent of the former. . . . Significant comparison of a particular type of behavior in two different species is impossible unless and until the behavior has been adequately analyzed in each species by itself.

This hypothesis is conditional on the existence (or availability) of animal models to accurately mimic human psychiatric conditions. In reality, the overwhelming majority of mental disorders recognized by DSM, the International Statistical Classification of Diseases and Related Health Problems (published by the World Health Organization), and the American Psychiatric Association do not have a counterpart in laboratory animals. For those human conditions that are considered to have animal homologues, there often exist critical causal mechanisms that differ between humans and animals, which raise methodological questions about the soundness and relevance of these animal models.¹⁵

Because of the multifactorial nature of conditions such as depression and anxiety and the ambiguities inherent in psychiatric diagnosis and treatment, the use of animal models in psychiatry presents unique challenges-unlike those found in other medical disciplines. In most cases, animal models represent a compromise because the cause and mechanism of the human condition under investigation may not be fully understood. In addition, researchers are using a relatively simple system (receptor activation or inactivation) to represent a more complex and less readily studied system (human mental disorders). While examples can be found to demonstrate common and conserved modes of action of neurotransmitter chemicals throughout phylogenetically remote organisms, this approach has its limits when studying complex systems, such as the human CNS.¹⁶ According to molecular biologist Marc van Regenmortel¹⁷:

The reductionist method of dissecting biological systems into their constituent parts has been effective in explaining the chemical basis of numerous living processes. However, many biologists now realize that this approach has reached its limit. Biological systems are extremely complex and have emergent properties that cannot be explained, or even predicted, by studying their individual parts. The reductionist approach-although successful in the early days of molecular biology-underestimates this complexity and therefore has an increasingly detrimental influence on many areas of biomedical research, including drug discovery and vaccine development.

Animal models, in general, have not been subjected to the rigors of evidence-based medicine. Few systematic reviews or meta-analyses have been conducted to compare treatment outcomes in laboratory animals with outcomes in clinical trials. Overall, the animal model has performed poorly as a predictive modality of human outcome in these reviews.^18-22

Examples of animal models in psychiatry

Behavioral despair. The behavioral despair model is commonly used to screen candidate antidepressants. Like other TCAs, imipramine was screened using the Porsolt forced swim test. In this test, the animal (a rat or a mouse) is placed in a container with cold water and is forced to swim until exhausted; it is then briefly taken out of the water. This is repeated until the animal reaches a state of helplessness and stops swimming. Although immobility time is reduced by antidepressant agents such as imipramine, significant strain differences have been reported.²³

The Porsolt forced swim test has been criticized on the grounds that the state of helplessness is more a strategy of survival than a sense of “despair.” The increased immobility simply demonstrates a positive behavioral adaptation, in which the animal has learned that it cannot escape and is conserving energy until it is removed from the water. In addition, while the test is reported to distinguish antidepressants and neuroleptics from anxiolytics, false positives have been reported for a number of other compounds, including stimulants, convulsants, anticholinergics, pentobarbital, and opiates.^24,25

Canine acral lick dermatitis. This is considered by some researchers to be a suitable animal model for the study of obsessive-compulsive disorder (OCD) in humans.²⁶ However, most cases of acral lick dermatitis in animals have an underlying allergic cause; if the allergen is eliminated, the condition resolves. In humans, OCD is an anxiety disorder characterized by intrusive thoughts, unrelated to allergies. Although SSRI treatment may be effective for both acral lick dermatitis in animals and OCD in humans because of a shared neurotransmitter response, this does not confer homology on the animal model. According to Nonneman and Woodruff,²⁷ “If every aspect is fully isomorphic between the animal model and the human condition, including cause and mechanism, the model is homologous.” Clearly, the OCD dog model does not fulfill these criteria. In addition, the dog model ignores the existence of a genetic component and the presence of comorbidities, which are thought to play an important role in human OCD.^28,29

Transgenic mice and the study of anxiety-like endophenotypes. Humans and mice share approximately 97% of their working DNA and approximately 24,000 genes per body cell.³⁰ In light of these facts, scientists have turned their attention to the study of differential gene expression patterns in genetically altered mice to investigate anxiety through the corticotropin-releasing hormone system, the serotonin system, and the GABA system.³¹ However, because genes work in networks and animals are examples of complex systems, small changes at the gene level can have major consequences for the individual. Thus, it is irrelevant to point to observed similarities in genetic makeup (including transgenes) between species, since the details of the differences are in the interactions between conserved genes, not in the genes themselves.³²

As Hirst and colleagues³³ have shown in the example of the serotonin system, it is unlikely that serotonin type 6 knockout mice will be useful for validating the serotonin type 6 receptor as a therapeutic target because of unexpected species differences in both receptor regional distribution and pharmacological profiles. It is now evident that slight variations in rodent and human amino acid sequences can lead to unexpectedly large differences in the pharmacology of the receptors, with potentially disastrous effects for drug development. What has not been clearly documented until the study by Hirst and colleagues is that mouse receptors could be significantly different from rat receptors.

Role of non-human primates in psychiatric and neurological research. The use of non-human primates by Harlow and associates³⁴ to demonstrate the effects of maternal deprivation has been well documented. In experiments conducted between 1957 and 1963, they removed baby rhesus monkeys from their mothers and observed the effects of partial and total social isolation. Some of the monkeys were kept in solitary confinement for up to15 years. These studies have been criticized on both ethical and methodological grounds.¹⁵

Diagnosing “depression” in a monkey is at odds with the successful ongoing process of clarifying psychiatric diagnoses by using DSM criteria. It is not possible to ascertain feelings of worthlessness and excessive guilt, indecisiveness, and thoughts of death from observations of monkeys.³⁵ Harlow’s student Stephen Suomi became more circumspect in 1995, when he carefully referred to the condition in monkeys as “something equivalent to depression” rather than “depression.”

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