The role of rodent models in the discovery of new treatments for schizophrenia: updating our strategy.

The strategies used in preclinical research in schizophrenia have evolved from experiments focused on the pharmacology of existing antipsychotic or psychotomimetic drugs to the broader study of pharmacological modulation of the neurobehavioral systems affected in schizophrenia. As an additional approach, neurodevelopmental, including genetic, manipulations have become increasingly used to model disease risk factors or to induce schizophrenia-relevant neuropathology. In the vast majority of these models, behavioral testing paradigms are used to test the effects of the drugs or developmental manipulations on psychomotor, cognitive and affective processes hypothesized to be affected in schizophrenia. The term "animal model of schizophrenia" is now applied to any combination of these strategies. The expansion in animal modeling strategies has led to significant innovation in identifying novel neural mechanisms that may contribute not only to psychosis but also to the cognitive and negative symptoms of schizophrenia. Yet one cost of innovation in the discovery of truly novel treatment targets is a higher risk for false positives--drugs that have shown promise in animal models but not in clinical trials. The goals of this commentary are to first provide a brief history and conceptualization of rodent models in preclinical research and then examine the issues to be addressed in order to increase the predictive power of animal models in the identification of new treatment targets and, ultimately, new effective treatments for schizophrenia.