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antidepressant in 1957.2,3 MAO inhibitors originated from an effort to develop antituberculosis medications; they were superseded by tricyclic antidepressants (TCAs), which were discovered by clinical observation.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
1. Bernard C. An Introduction to the Study of Experimental Medicine. Greene HC, trans. New York: Macmillan & Co, Ltd; 1927.
2. Waterstradt K. A transitory psychosis occurring twice after isoniazid therapy [in German]. Dtsch Med Wochenschr. 1957;82:1138.
3. Jackson SL. Psychosis due to isoniazid. Br Med J. 1957;2:743-746.
4. Charpentier P, Gailliot P, Jacob R, et al. Recherches sur les dimé-thylaminopropyl-N phénothiazines substituées. Comptes rendus de l’Académie des sciences (Paris). 1952;235:59-60.
5. Laborit H, Huguenard P, Alluaume R. Un noveau stabilisateur végétatif (le 4560 RP). Presse Med. 1952;60:206-2088.
6. Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2:349-352.
7. Sternbach LH. The discovery of Librium. Agents Actions. 1972;4:193.
8. Preskorn SH. CNS drug development. Part I: the early period of CNS drugs. J Psychiatr Pract. 2010;16:334-339.
9. Preskorn SH. CNS drug development. Part II: advances from the 1960s to the 1990s. J Psychiatr Pract. 2010;16:413-415.
10. Senay EC. Toward an animal model of depression: a study of separation behavior in dogs. J Psychiatr Res. 1966;4:65-71.
11. McKinney WT Jr, Bunney WE Jr. Animal model of depression. I. Review of evidence: implications for research. Arch Gen Psychiatry. 1969;21:240-248.
12. Dinsmoor JA, Bonbright JC Jr, Lilie DR. A controlled comparison of drug effects on escape from conditioned aversive stimulation (“anxiety”) and from continuous shock. Psychopharmacologia. 1971;22:323-332.
13. Bliss EL, Zwanziger J. Brain amines and emotional stress. J Psychiatr Res. 1966;4:189-198.
14. Beach FA. Animal models for human sexuality. Ciba Found Symp. 1978;(62):113-143.
15. Cohen M. A critique of maternal deprivation experiments on primates. http://www.mrmcmed.org/mom.html. Accessed December 19, 2011.
16. Garcia-Reyero N, Habib T, Pirooznia M, et al. Conserved toxic responses across divergent phylogenetic lineages: a meta-analysis of the neurotoxic effects of RDX among multiple species using toxicogenomics. Ecotoxicology. 2011;20:580-594.
17. Van Regenmortel MH. Reductionism and complexity in molecular biology. Scientists now have the tools to unravel biological and overcome limitations of reductionism. EMBO Rep. 200;45:1016-1020.
18. Knight, A. Systematic reviews of animal experiments demonstrate poor contributions toward human healthcare. Rev Recent Clin Trials. 2008;3:89-96.
19. Knight A, Bailey J, Balcombe J. Animal carcinogenicity studies: implications for the REACH system. Altern Lab Anim. 2006;34(suppl 1):139-147.
20. Lindl T, Voelkel M, Kolar R. Animal experiments in biomedical research. An evaluation of the clinical relevance of approved animal experimental projects [in German]. ALTEX. 2005;22:143-151.
21. Perel P, Roberts I, Sena E, et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ. 2006;334:197.
22. Pound P, Ebrahim S, Sandercock P, et al; Reviewing Animal Trials Systematically (RATS) Group. Where is the evidence that animal research benefits humans? BMJ. 2004;328:514-517.
23. Porsolt RD, Bertin A, Jalfre M. “Behavioural despair” in rats and mice: strain differences and the effects of imipramine. Eur J Pharmacol. 1978;51:291-294.
24. Borsini F, Meli A. Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology (Berl). 1988;94:147-160.
25. Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther. 1977;229:327-336.
26. Stein DJ. An animal model of obsessive-compulsive disorder. Arch Gen Psychiatry. 1992;48:517-521.
27. Nonneman AJ, Woodruff ML, eds. Animal models and the implications of their use. Toxin-Induced Models of Neurological Disorders. New York: Springer; 1994.
28. Rasmussen SA. Genetic studies of obsessive compulsive disorder. In: Hollander E, Zohar J, Marazziti D, Oliver B, eds. Current Insights in Obsessive Compulsive Disorder. Chichester, England: John Wiley & Sons; 1994:105-114.
29. Mineka S, Watson D, Clark LA. Comorbidity of anxiety and unipolar mood disorders. Annu Rev Psychol. 1998;49:377-412.
30. Church DM, Goodstadt L, Hillier LW, et al; Mouse Genome Sequence Consortium. Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol. 2009;7:e1000112. doi:10.1371/journal.pbio.1000112.
31. Bakshi VP, Kalin NH. Animal models and endophenotypes of anxiety and stress disorders. In: Davis KL, Charney D, Coyle JT, Nemeroff C, eds. Neuropsychopharmacology. The Fifth Generation of Progress. New York: Raven Press/American College of Neuropsychopharmacology; 2002:883- 900.
32. Shanks N, Greek R. Animal Models in Light of Evolution. Boca Raton, FL: Brown Walker; 2009.
33. Hirst WD, Abrahamsen B, Blaney FE, et al. Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling. Mol Pharmacol. 2003;64:1295-1308.
34. Harlow HF, Dodsworth RO, Harlow MK. Total social isolation in monkeys. Proc Natl Acad Sci U S A. 1965;54:90-97.
35. Psychiatric Disorders. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). AllPsych Online. http://allpsych.com/disorders/dsm/html. Accessed May 4, 2011.
36. Crick F, Jones E. Backwardness of human neuroanatomy. Nature. 1993;361:109-110.
37. Kreiman G, Fried I, Koch C. Single-neuron correlates of subjective vision in the human medial temporal lobe. Proc Natl Acad Sci U S A. 2002;99:8378-8383.
38. de Graaf-Peters VB, Hadders-Algra M. Ontogeny of the human central nervous system: what is happening when? Early Hum Dev. 2006;82:257-266.
39. Kreiman G. Single unit approaches to human vision and memory. Curr Opin Neurobiol. 2007;17:471-475.
40. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Development Safety Update Report. August 17, 2010.
41. Shanks N, Greek R, Greek J. Are animal models predictive for humans? Philos Ethics Humanit Med. 2009;4:2.
42. Suter K. What can be learned from case studies? The company approach. In: Lumley C, Walker S, eds. Animal Toxicity Studies: Their Relevance for Man. Lancaster, England: Quay Publishing; 1990:71-78.
43. Fletcher AP. Drug safety tests and subsequent clinical experience. J R Soc Med. 1978;71:693-696.
44. Lumley C. Clinical toxicity: could it have been predicted? Pre-marketing experience. In: Lumley C, Walker S, eds. Animal Toxicity Studies: Their Relevance for Man. Lancaster, England: Quay Publishing; 1990:49-56.
45. Olson H, Betton G, Robinson D, et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol. 2000;32:56-67.
46. Balcombe JP, Barnard ND, Sandusky C. Laboratory routines cause animal stress. Contemp Top Lab Anim Sci. 2004;43:42-51.
47. Zinberg NE, Robertson JA. Drugs and the Public. New York: Simon and Schuster; 1972.
48. Hurst JL, West RS. Taming anxiety in laboratory mice. Nat Methods. 2010;7:825-826.
49. Longordo F, Fan J, Steimer T, et al. Do mice habituate to “gentle handling?” A comparison of resting behavior, corticosterone levels and synaptic function in handled and undisturbed C57BL/6J mice. Sleep. 2011;34:679-681.
50. Nakayasu T, Kato K. Is full physical contact necessary for buffering effects of pair housing on social stress in rats? Behav Processes. 2011;86:230-235.
51. Ghaemi SN. A Clinician’s Guide to Statistics and Epidemiology in Mental Health: Measuring Truth and Uncertainty. New York: Cambridge University Press; 2009.
52. Engel GL. The need for a new medical model: a challenge for biomedicine. Science. 1977;196:129-136.
53. Grinvald A, Hildesheim R. VSDI: a new era in functional imaging of cortical dynamics. Nat Rev Neurosci. 2004;5:874-885.
54. Janssen P, Srivastava S, Ombelet S, Orban GA. Coding of shape and position in macaque lateral intraparietal area. J Neurosci. 2008;28:6679-6690.
55. Van Essen DC, Lewis JW, Drury HA, et al. Mapping visual cortex in monkeys and humans using surface-based atlases. Vision Res. 2001;41:1359-1378.
56. Oldham MC, Konopka G, Iwamoto K, et al. Functional organization of the transcriptome in human brain. Nat Neurosci. 2008;11:1271-1282.
57. Hall SD, Barnes GR, Furlong PL, et al. Neuronal network pharmacodynamics of GABAergic modulation in the human cortex determined using pharmaco-magnetoencephalography. Hum Brain Mapp. 2010;31:581-594.
58. Barnes D. The use of nonhuman animals in psychobiological and behavioral research. In: Natelson NB, Cohen MJ, eds. In: Proceedings from Future Medical Research Without the Use of Animals: Facing the Challenge; May 15-16, 1990; Tel Aviv, Israel.
59. Gallup GG Jr. Chimpanzees: self-recognition. Science. 1970;167: 86-87.
60. Kaneko T, Tomonaga M. The perception of self-agency in chimpanzees (Pan troglodytes). Proc Biol Sci. 2011 May 4; [Epub ahead of print].
61. Goodall J. A plea for the chimps. New York Times Magazine. May 17, 1987:108-110.
62. Panksepp J. Neuroevolutionary sources of laughter and social joy: modeling primal human laughter in laboratory rats. Behav Brain Res. 2007;182:231-244.
63. Panksepp J. Toward a science of ultimate concern. Conscious Cogn. 2005;14:22-29.