Clinical trials involving brain disorders are notoriously difficult to set up and run. Innovative ways to develop effective prevention and treatment strategies for central nervous system (CNS) diseases are urgently needed. New approaches that are likely to renew or at least modify the paradigms used so far have been recently proposed. Quantitative systems pharmacology (QSP) uses mathematical computerized models to characterize biological systems, disease processes and CNS drug pharmacology. Integrated experimental medicine should increase the probability and predictability of success while controlling clinical trials costs. Finally, the societal perspective and patient empowerment also offer additional approaches to demonstrate the benefit of a new drug in the CNS field.