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The identification of drugs to treat major psychiatric disorders launched the fields of biological psychiatry, behavioral pharmacology, and neuropsychopharmacology. It had a profound impact not only on individuals suffering from these disorders and on the care and hospitalization of patients but also on the emergence of entirely new disciplines. The astute observations in the clinical setting that led to the first generation of psychoactive drugs created the putative framework for the potential discovery of new generations of psychotropic agents. The key challenge in the search for a new generation of improved psychoactive drugs has focused on: enhanced validation of the animal models used to characterize new chemical entities (NCEs) as bona fide models of the human disease and the use of these models to effectively translate NCEs to the human disease state. The learning curve for CNS research focuses on the unique complexity of the brain.