Experimental Disease Models

Schizophrenia is clearly a disorder with a primary impact on higher cognitive function. Therefore, the modeling of this disorder in less cognitively developed species than human represents a significant challenge. The validity of an animal model for any disorder can be rated on three scales: predictive, construct, and face validity.

'Predictive validity' focuses on how well results produced in the animal model are borne out in the clinic. More often, and particularly in the case of schizophrenia, animal models are back-validated using clinical benchmarks to provide a basis for arguing for future predictive validity. While this reasoning seems to hold for recent atypical antipsychotics in that they produce preclinical effects similar to that observed for older atypicals, the fact that these newer compounds are largely subtle variations on the clozapine theme discussed above raises questions regarding the usefulness of this back-validation. This is a significant caveat in that there is little confidence that a truly novel antipsychotic medication will appear as a positive in available preclinical models.

'Construct validity' has to do with the theoretical rationale underlying the model. A model with a high degree of construct validity would disrupt the same neurotransmitter systems and engage the same neuronal circuitry as the human disorder. Based on recent imaging studies and measurement of biological markers, there is an increased confidence that many of the pharmacological models of schizophrenia have a reasonable degree of construct validity. However, it is important to note that all of the pharmacological models currently employed are based primarily on the psychotomimetic properties of the compounds in humans. The inability to assess psychosis in rodents treated with these psychotomimetics thus raises an issue of face validity.

'Face validity' is a measure of how accurately the model reproduces the symptoms of the human disorder. This is particularly difficult in schizophrenia as many, if not all, of the symptoms are either uniquely human, or are impossible to probe in an animal mode.

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