William Maria*
With the failure rate of clinical trials for CNS illnesses reaching all-time low, new strategies are needed to reverse the trend. This paper looks back at the recent history of CNS drug development and proposes a new paradigm based on what has been learned. Following the initial wave of breakthrough therapies identified by detailed clinical observations, an emphasis on a phenotypic target-agnostic technique emerged, often resulting to beneficial pharmaceuticals with a diverse pharmacology. Because these highly selective molecules are unlikely to address the complex pathological phenotypes of most CNS disorders, the subsequent introduction of molecular biology and a focus on a target-driven strategy has largely dominated drug discovery efforts, but has not increased the probability of success. The use of preclinical animal models has lacked robust translational power in several circumstances. Quantitative Systems Pharmacology (QSP), a mechanism-based computer model of biological processes informed by preclinical information and strengthened by neuroimaging and clinical data, may be a new potent knowledge generation engine and paradigm for rational polypharmacy.
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