Advancing experimental therapeutic trials with repurposed drugs. Given the time frame, cost, and failure rate of traditional drug development efforts with new chemical entities, one expedient path toward therapeutics for neuropsychiatric disorders may be to repurpose an already existing approved drug. To this end, through our chemical genomic screening platform in conjunction with our patient-specific stem cell models, rodent neuron, and biochemical studies, we have identified multiple F.D.A.-approved drugs and compounds currently under clinical investigation that are candidates for repurposing studies. For example, for bipolar disorder, based upon our studies on the regulation of WNT signaling by the mood stabilizer lithium (Pan et al., Neuropsychopharmacology, 2011) and our high-throughput screens for lithium ‘enhancers and mimetics’ (James et al. Science Signaling 2009; Biechele et al. Chemistry & Biology, 2010; Zhao et al. Journal of Biomolecular Screening, 2012), we have discovered that HMG-Co-A reductase inhibitors (e.g. simvastatin (Zocor)) and the drug riluzole (Rilutek) used to treat amyotrophic lateral sclerosis are both capable of enhancing WNT signaling, a major pathway controlling adult neurogenesis in the hippocampal dentate gyrus. Similarly, with the goal of rapidly advancing the translation of novel therapeutics for frontotemporal dementia (FTD), using our human iPSC models that we recently developed (Silva et al. Stem Cell Reports, 2016) we have screened for and identified multiple F.D.A. approved drugs capable of causing tau clearance in human neurons through autophagy-dependent and independent mechanisms. In collaboration with our clinical colleagues at MGH we are planning to perform pilot clinical trials to advance testing of these therapeutic concepts in patients.