Psychiatric Disorders "I cannot recall a single instance where my clinical judgment was even remotely influenced by the results of a psychological study using animals as subjects or 'models."---Michael Klaper, M.D.

"The similarity of animal models to psychiatric disorders has often been exaggerated, and attempts to mirror syndromes such as 'depression' or 'psychosis' in animals have generally failed. Thus, it is time to reevaluate existing animal models and develop novel behavioral approaches." National Institute of Mental Health (NIMH) Psychiatrists are barely willing to accept animal experiments as relevant to human mental disorders; they often do not know or ignore them. Nevertheless, animal studies, conducted to understand human behaviors and mental disorders, have flourished and animal models were created for this purpose. Psychologists, psychiatrists and sociologists study human behaviors either in individuals or groups and analyze the disorders or deviancies that according to society's standards we judge abnormal. With regard to medical research, other scientists have raised animal psychology to the status of a science. The use of animals in behavioral research is controversial in a sense that its purpose is the study of animal models in order to know better the psychology of human beings and find treatments for mental disorders. Many investigators have engaged in the slippery road of animal-based experimentation. Using animals as models of a human pathology is an approach where the questions under study are specific to remain within their own limits of validity. These limits are the reasons why animal experimentation is subject to criticism. When it comes to the study of human pathologies, the findings in animals are quite different and extrapolation of animal data to humans becomes an art in subjectivity but not a science. In addition, the discrepancies between humans and non-human mammals makes the process of deciding a possible trial in human subjects an estimate of what might be the very first meaningful experiment. Based on animal data, future clinical investigations may work or it may not work; the outcome amounts to a game of chance. Neurosis defines a set of abnormal emotions that are manifested by exaggerated feelings. The causes of neurosis have multiple roots to be found in conflicts, childhood or unconscious events, and result in different forms of psychopathologies including anxiety, hysteria, phobia, obsessive-compulsive behaviors and depersonalization. In 1772, neurosis was first used by a Physician in Edinburgh named Cullen to denote a condition arising from an affliction of the nervous system that was synonymous with the term 'functional nervous illness' until the 1930s. Epidemiological studies showed that minor neurosis is common in the general population, and the most frequent symptoms of these minor disorders are anxiety, depression, irritability, insomnia and fatigue. Research consultant for the Research Animals Department of the RSPCA, Sheila Silcock, wrote in 1992: "Researchers believe that we need to understand the brain mechanisms underlying anxiety and depression in animals in order to design better drugs to treat the same conditions in the patients. But some therapists would argue that anxiety and depression are responses to social circumstances rather than organic diseases, and so research using animals is not appropriate."(1)With regard to anxiety and depression, twice as many women as men take tranquilizers, and there is a similar trend in the use of antidepressants; one important question is to know whether the imbalance is initiated in their minds or in their environment. Stress is a risk factor that can create reactions such as agitation, ill-adapted responses to the surroundings, stupor and usually psychotherapies and anxiolytic drugs, in the most severe forms, can alleviate some of the symptoms. Painful experiences such as the loss of a beloved one, war or physical injury can cause traumatic stress disorders including poor concentration, avoidance, distressing dreams, which can be treated by supportive therapy and anxiolytic medication. Also, childhood is a powerful period of our life defining the development of neurosis in adult life and affecting our personality. Stressful working conditions, unemployment and isolation can predispose to neurosis. It is not excluded that genetic factors are involved in the onset of neurotic behaviors. It is impossible to create a model of neurotic animal, first based on the many external factors as described above and secondly because of the problem of measuring the emotional responses in animals. What was often interpreted as reactions of neurosis was in fact a reaction of fear, politely called 'generalized conditional emotional response'(CER). For example, animals can be accustomed to their experimental environment but as soon as the CER is induced by various means, the stressed animals attempt to escape from the restraining apparatus. In cases where the animal cannot escape, like the sows locked in their gestation crates to deliver sausage-making piglets, the animals develop abnormal behaviors. The sows rub their snout back and forth across the front of the crate and repeatedly bite the metal bars, as do mice and rabbits in their cages. Studies showed that these repetitive movements or stereotypies might stimulate the release of endorphins in the sow's brain. This "self-administration" of those natural chemicals may induce a state of temporary relief from the torments of crate confinement. Frustrated farm animals, for instance, pushed to the point of madness, can develop abnormal motor or autonomic reactions leading to a general impairment of excitatory and inhibitory processes. In industrialized farms, pigs are often subject to heart attacks due to the brutal handling and acute fear they experience. These conditions lead to a pathology that may resemble the development of chronic psychiatric disorders in humans. However, pigs are not used as models of neurosis. Maybe the reason is that it would be unethical to create in a modern laboratory the degree of inhumanity that goes on in the factory farms. Psychosis is due to anxiety and the symptoms resemble those of neurosis but form different patterns persistent in duration from months to years. The symptoms involved a set of psychological and physical disorders; symptoms are related to the gastrointestinal tract (e.g. dry mouth, aerophagy), respiratory problems (e.g. constriction in the chest, overbreathing), cardiovascular disorders such as palpitations and a feeling of discomfort in the chest. Anxiety is common to many psychiatric disorders such as depression and schizophrenia. Delusions, hallucinations are well known and stress is a major factor that has an important etiologic role. In animal models of psychosis, drugs (e.g. LSD and amphetamines) are used to induce disrupted mental states but also social isolation of young primates had been studied. Social isolation will result in severe behavioral defects in which the animals rock and refuse to interact with other members; they show stereotypies and can develop aggressive behaviors. Isolation is long known to be the cause of severe psychological imbalance in the young child and it is thought that the child is overwhelmed by the stimulation created by separation from the mother. In 1969, researcher Bowlby elaborated the idea that this stressful event had subsequent repercussions in adulthood and is enhanced by social problems. (2)The intensive use of primates, such as the isolation-reared monkey model, did not advance our undertanding of the cause of the disorders in humans and attempts to reverse the negative effects of the psychosis were unsuccessful. In this model of mother-infant separation and in the light of the well documented existing maternal bonds in monkeys, the procedure was not only stressful-which was the intended stimulus-but cruel. The methodology was adapted to the model of infant-infant separation that was reported by Suomi in 1972. (3)Researchers looked at reproducing in those monkeys a state that was already well documented in humans a long time ago. In fact, it was shown that a cumulative effect of repetitive infant-infant separation caused an arrest of the maturation of social development as exhibited by the monkeys isolated from their mothers during the first 3 to 6 months of life. In a recent study that aimed at measuring the cerebrospinal fluid concentrations of biogenic amines and metabolites, a stressed pregnancy condition consisted of relocating the pregnant females to a darkened room and by eliciting a startle response via an alarm horn, which sounded three times randomly, 1 second per sounding, during a 10-minute period to create a model of chronic unpredictable stress. At 8 months of age, the offspring was subjected to conditions of separation from peer cage mates.(4) The question that taxpayers should be asking could be put this way: do we have to support a research that investigates an obvious fact or that brings minor information? Let alone the important question of validity, the above published research paper originated from an institution that had consistently reported zero animals under the category of unalleviated pain and distress while it was obvious that such research resulted in some degree of distress but it was not presented as so by the institution. Because dysfunction of the amygdala in the brain is implicated in emotional discharges such as anxiety, depression and because bilateral amygdala damage in humans are associated with impaired ability in judging facial expressions and making accurate judgements, animal studies followed to confirm what was already known in human patients. At the Department of Psychiatry and Center for Neuroscience, University of California, researchers produced lesions in the brain of 2-week-old macaque monkeys who were returned to their mothers for rearing.(5) The authors observed that the mutilated animals, at 6-8 months of age, demonstrated less fear to unknown objects than normal control animals but more fear behaviors during social interactions. They also proposed that the lesions did not produce autistic-like behaviors in young monkeys. Even though autism is a terrible disability that needs to be better understood, the knowledge or the benefits that can be accrued from such experiment is irrelevant to the human pathology. In fact, our best understanding of the important functions of the brain in humans has come from clinical case studies and post-mortem analysis of the brain tissue. Moreover, autism-like behaviors, created artificially in monkeys cannot be described as a model of autism in children due to the complexity of the etiology of the disorder and also due to the lack of understanding of the etiology in the first place. Genetic, cortical and subcortical abnormalities, chromosomal defect and at a lesser extent poor social environment contribute to the development of autism. Through the management of the disease, educational programs and assisted teaching, there are opportunities to create sound research and find therapies while gaining a better understanding of the disease. Antidepressants are largely used to overcome stress and other psychological troubles. Blood analysis of patients to measure their levels of hormones or glucose is performed routinely everywhere and is a very useful tool for diagnosis. This is why studying the levels of molecules in the blood such as cortisol would not require the use of monkeys. Blood samples of patients under antidepressants should be easy to obtain in specialized institutions, during the course of a treatment and under informed consent. However, at the Department of Psychiatry, University of Colorado Health Sciences Center in Denver, it seems that researchers do not have this option.(6) Instead 9-months rhesus monkeys (Macaca mulatta) live in captivity to serve as blood donors. The findings demonstrated that plasma total immunoglobulins and cortisol levels were the lowest in monkeys treated with antidepressants regardless of specific drug treatments or early rearing conditions versus control animals. Whether there would be a similar situation in humans under the same conditions, we do not know of course, but based on animal data these researchers were confident that doctors should take into consideration their data when prescribing commonly used antidepressants for treatment of childhood disorders. Isn't that stretching the point a bit? If by any chance they happen to reproduce one or several symptoms, other means are available or can be investigated to replace the use of poor models. What is inflicted upon animals, in this field, today is no worse than the popular techniques in the 1960s and 1970s that included giving rats or dogs electric shocks and burning their footpads to elicit certain behaviors such as aggression and helplessness. These are models that many researchers disapprove now not only because they are cruel but also because they are scientifically invalid and we can reasonably wonder what motivated a few ill-inspired persons to adopt such models. They were so unnatural that they could not lead to significant results. Another psychosis such as maniac-depression induces changes in emotional responses influenced by the environment. In some cases, certain reflexes including escape and defensive behaviors become abolished. For example, it is possible in some models to trigger an inhibition of a normal defensive reaction by creating a state of learned helplessness in which the animals receive electric shocks or are placed in an environment that imposes an inescapable constraint. The animal does not respond to stress and pain anymore as Claude Bernard noted in his experimental animals during surgery. Dogs upon receiving electric shocks do not respond any longer after sometime; they exhibit a passive state unless they are trained to make the appropriate response that would stop the shocks. Similarly, rats placed in a tank of water with no chance to escape let themselves die. Rats are good swimmers but swimming up to 60 hours, even when given a chance to have a rest period, is obviously more than a rat can take. Attempts to reverse the effects of this stressful stimulus (i.e. a swim beyond 60 hours) failed and the Olympic performance of the rat did not match the expectations of its trainer. Did the rats commit a suicide in a way people commit suicide, shall we ask? In this example, it is difficult to understand how the rationale connects to anything sound in that nutty experimental design. The conclusion was: rats can drown under experimental conditions. Learned helplessness is still used today to test antidepressant treatments and the model of forced swimming tests in rats still exists.(7) Some already known antidepressants, such as imipramine or clomipramine, are being studied to test their properties as to how they reverse the effects of learned helplessness and reduce the escape failures or immobility when the animals are trained to learn a new escape task. As well, pharmacological studies indicated that repeated administration of antidepressants, at some extent, reduces helpless behaviors. That is the reason why these models are still investigated to screen antidepressant drugs and help understand the pathophysiology of the stress-induced behavior. Mental diseases are not well understood in terms of pathophysiology and this makes the comparison of animal models to the human disorders difficult if not impossible. Without a basic understanding of the underlying mechanisms having an etiologic role in the onset and course of human psychological disorders, finding an animal model that would present similar mechanisms still remains a challenge. A second problem is raised when we want to relate such mechanisms, underlying abnormal animal behaviors, with those of psychological disorders that can hardly be compared. More modern methodologies rely on functional genomics, which is the study of the relationship between gene identification and the linkage to pathological or normal biological events. A recent study proposed, in a rat model of metamphetamine-induced psychosis,(in which gene expression was measured by using a microarray of 8000 genes) that a G-protein was more expressed than in control animals. Also, its related gene was identified in the rat chromosomes. The authors found an analogous location in the human genome that is associated with schizophrenia, a susceptibility gene candidate similar to a gene whose expression is stimulated after metamphetamine treatment in rat. (8)According to the authors, the experiment strengthens the claim that the metamphetamine-induced animal psychosis is a model of schizophrenia. Schizophrenia is characterized by a faulty reality sense, delusions, hallucinations, personality change and as well inhibition of defensive behaviors. The tendency is hereditary but is influenced by psychological factors. In experimental animals, schizophrenic animals were produced either by isolation or by drug treatment such as amphetamines. Under low doses of amphetamines, animals are excited and agitated similarly to humans under the central stimulant actions of the drug. For instance, chimpanzees intoxicated with amphetamines exhibit purposeless searching and grooming behaviors as seen in human amphetamine addicts. 1.Sheila Silcock. "Is your experiment really necessary?" New Scientist, 18 April (1992) 2. Bowlby J. "Psychopathology of anxiety: the role of affectional bonds." In Studies in anxiety (ed. M. H. Lader). British Journal of Psychiatry Special Publication No.3, London (1969) 3. Suomi S. J. et al. Am J Psychiatry, 128: 927 (1972). 4. "Prenatal stress alters brain biogenic levels in primate." Development and Psychopathology, 10(3), pp. 427-440 (1999) 5. Prather M. D. et al. "Increased social fear and decreased fear of objects in monkeys with neonatal amygdala lesions." Neuroscience 106(4):653-8 (2001) 6. Laudenslager M. L. et Clarke A. S. "Antidepressant treatment during social challenge prior to 1 year of age affects immune and endocrine responses in adult macaques." Psychiatry Res Jul 24;95(1):25-34 (2000) 7. Kazuaki T. et al. "Availability of learned helplessness test as a model of depression compared to a forced swimming test in rats." Pharmacology 63: 147-153 (2001). 8. Carol A. Tammings. "Genetic testing and Animal models." Am J Psychiatry 158:10 (2001) Further readings: Animal Models of Human Psychology, Critique of Science Ethics and Policy. Kenneth J. Shapiro (1998) Hogrefe &Huber Publishers.