Criteria of validity for animal models of psychiatric disorders: focus on anxiety disorders and depression

Abstract

Animal models of psychiatric disorders are usually discussed with regard to three criteria first elaborated by Willner; face, predictive and construct validity. Here, we draw the history of these concepts and then try to redraw and refine these criteria, using the framework of the diathesis model of depression that has been proposed by several authors. We thus propose a set of five major criteria (with sub-categories for some of them); homological validity (including species validity and strain validity), pathogenic validity (including ontopathogenic validity and triggering validity), mechanistic validity, face validity (including ethological and biomarker validity) and predictive validity (including induction and remission validity). Homological validity requires that an adequate species and strain be chosen: considering species validity, primates will be considered to have a higher score than drosophila, and considering strains, a high stress reactivity in a strain scores higher than a low stress reactivity in another strain. Pathological validity corresponds to the fact that, in order to shape pathological characteristics, the organism has been manipulated both during the developmental period (for example, maternal separation: ontopathogenic validity) and during adulthood (for example, stress: triggering validity). Mechanistic validity corresponds to the fact that the cognitive (for example, cognitive bias) or biological mechanisms (such as dysfunction of the hormonal stress axis regulation) underlying the disorder are identical in both humans and animals. Face validity corresponds to the observable behavioral (ethological validity) or biological (biomarker validity) outcomes: for example anhedonic behavior (ethological validity) or elevated corticosterone (biomarker validity). Finally, predictive validity corresponds to the identity of the relationship between the triggering factor and the outcome (induction validity) and between the effects of the treatments on the two organisms (remission validity). The relevance of this framework is then discussed regarding various animal models of depression.

Figure 1

A framework for animal models. Animal models are not just organisms supposed to resemble a human dysfunction: the processes by which both animal and humans fall into this state must also be similar. Here is a simplified representation of how this occurs.

Figure 2

Criteria of validity for animal models. A comparison between the general process of the human disease (on the lower plane) and its animal model (on the higher plan). The orthogonal black arrows link the crucial points of similarity between the parallel processes and represent the different criteria of overall validity for animal models (or the various kinds of validity according to which an animal model ought to be designed).

Figure 3

A comparison between Willner's criteria and the present proposal. Willner's criteria are represented by the brown circles and our nine criteria are represented by squares with the same color code as in Figures 1 and 2. Where a square fully overlaps with one of Willner's criteria (or with one aspect of one of Willner's criteria) it is represented inside the corresponding circle. Where it partially overlaps, it sits astride the circle. Where the criterion (or an aspect of it) has not been described by Willner, it stands outside the circles. Arrows indicate which sub-aspect of Willner's criteria corresponds to our proposed criteria.