Animal models of CNS disorders

There is intense interest in the development and application of animal models of CNS disorders to explore pathology and molecular mechanisms, identify potential biomarkers, and to assess the therapeutic utility, estimate safety margins and establish pharmacodynamic and pharmacokinetic parameters of new chemical entities (NCEs). This is a daunting undertaking, due to the complex and heterogeneous nature of these disorders, the subjective and sometimes contradictory nature of the clinical endpoints and the paucity of information regarding underlying molecular mechanisms. Historically, these models have been invaluable in the discovery of therapeutics for a range of disorders including anxiety, depression, schizophrenia, and Parkinson's disease. Recently, however, they have been increasingly criticized in the wake of numerous clinical trial failures of NCEs with promising preclinical profiles. These failures have resulted from a number of factors including inherent limitations of the models, over-interpretation of preclinical results and the complex nature of clinical trials for CNS disorders. This review discusses the rationale, strengths, weaknesses and predictive validity of the most commonly used models for psychiatric, neurodegenerative and neurological disorders as well as critical factors that affect the variability and reproducibility of these models. It also addresses how progress in molecular genetics and the development of transgenic animals has fundamentally changed the approach to neurodegenerative disorder research. To date, transgenic animal modelshave not been the panacea for drug discovery that many had hoped for. However continual refinement of these models is leading to steady progress with the promise of eventual therapeutic breakthroughs.