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