Revitalizing psychopharmacology in the GWAS era: the potential of barcoded screening in drug discovery

The success of comprehensive genome-wide association studies has substantiated the multigenetic origin of most mental disorders, including schizophrenia, bipolar disorder, and major depression. Non-coding genetic variants are enriched mainly in regulatory regions of genes expressed in excitatory and inhibitory neurons and converge particularly on cellular pathways implicated in neurodevelopment and synaptic functions. Given the molecular and cellular complexity of mental disorders, classical 'single-drug-target-based' drug discovery has largely failed in delivering novel pharmacological treatment options. We believe that drug development for complex disorders requires a paradigm shift toward a 'phenotype or pathway focused' approach, which integrates multi-parametric assay technologies and stem technology to perform screening and lead compound validation with dramatically enhanced contextual specificity. Moreover, many existing drugs used to treat mental disorders display polypharmacological actions. Therefore, there is a demand for developing assay technologies capable of dissecting the complex modes of action of novel drug candidates in a cost-effective manner. Here, we review technological progress across various fields that hold promise in delivering future breakthrough treatments for mental disorders.