Animal models of diseases are widely used in the preclinical phase of drug development. They have a place in early human clinical psychopharmacology as well, in order to get early clues that contribute to establish the proof of concept (POC) already in healthy volunteers (HV). Different types of models are available (pharmacological or non-pharmacological provocation, models based on age-related characteristics). This review is focused on pharmacological models in HV, with the aim to identify the main issues raised by their use in pharmaceutical trials. The available models unevenly fulfil the requirements of face validity, sufficient response rate, test-retest consistence and responsiveness to reference drugs. Most of them have been developed in the purpose of pathophysiology studies, using rating instruments validated for clinical practice. Substantial progress could be made by adapting models to the specific requirements of pharmaceutical trials, including wider use of biomarkers. Characteristics that make models, as well as biomarkers, suitabLe for use in drug development are proposed. Despite obvious limitations, human models can significantly enhance the way phase I studies contribute to establish the POC, provided they are integrated into adapted phase I development plans. Their use as industrial tools for drug evaluation requires specific, dedicated development.
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