The validity of the animal model in regulatory toxicology
From a regulatory perspective, psychiatric drugs are required to undergo animal testing to demonstrate safety and efficacy.40 Safety relates to toxicity testing, which requires a rodent species (usually a rat) and a non-rodent species (usually a dog) to undergo single-dose (acute), repeated-dose, and long-term exposure to a candidate compound. The acute toxic dose (LD50) is the median lethal dose of a compound required to kill 50% of a group of test animals. Repeated-dose exposures usually require 14- to 28-day studies, while long-term exposure requires up to 90 days in the rat and up to 12 months in the dog. Significant variations in the toxicity profile of a test compound may occur because of species differences in absorption, distribution, metabolism, and excretion (ADME).
Human lethal overdose figures are compiled by national poisons information centers. These are empirical data obtained from human accidental or deliberate poisoning and overdose (A. Vale, personal communication, 2009). Human lethal overdose cannot be predicted from animal LD50 values (Table). Animal studies are in fact poor predictors of human outcome with respect to drug toxicity.41-44The use of retrospective correlation is often inadvertently confused with prediction.
A classic study by Olson and colleagues45 looked at the concordance between adverse events seen in humans and data obtained from preclinical animal toxicity studies. While this study measured sensitivity, it ignored specificity; therefore, its conclusions are largely irrelevant to the great prediction debate.32 Although this study has been quoted in support of animal use as a predictive modality, Olson45 stated that “this study did not attempt to assess the predictability of preclinical experimental data to humans.”
In addition to the challenges presented by differences in ADME between species, other variables can influence the outcome of animal studies. The laboratory environment is inherently stressful for the animals. In addition to caged housing, which provides little or no environmental enrichment, even routine procedures can lead to significant changes in physiological parameters correlated with stress (eg, serum or plasma concentrations of corticosterone or glucose, heart rate, and blood pressure).46 While these changes may not be considered to be of much significance with respect to routine drug testing, the same cannot be said of drugs specifically designed to treat stress and similar conditions. According to Zinberg and Robertson,47 the difference between an animal’s natural setting and an artificial laboratory environment cannot be underestimated; it may produce major pharmacological effects. Variables such as group housing versus single housing, type of bedding, light-dark cycle, and handling by humans can affect the outcome of a study.48-50
Evidence-based medicine aims to apply the best available evidence gained from the scientific method to clinical decision making. Clinical research is the solid ground of medicine, whereas biological theory is a necessary but changing superstructure.51 In an era of the human genome and advanced noninvasive screening techniques, it is perhaps timely to examine the relevance of the animal model in modern psychiatry. This becomes all the more interesting when we consider the notion that psychiatry is the only medical discipline that attempts to treat a conceptual abstraction—namely the human mind—in addition to organs and physiological processes.15 Although molecular psychiatry provides some insight into the mechanism of mental illness, external psychosocial factors that influence human behavior fall well outside of its scope.52
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.